TRPV1 antagonists including dihydroxy substituent and uses thereof

ABSTRACT

The disclosure relates to Compounds of Formula (I) 
                         
and pharmaceutically acceptable derivatives thereof, where R 1 , R 4 , R 8 , R 9 , and m are as defined herein, compositions comprising an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof, and methods for treating or preventing a condition such as pain, pain associated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS, comprising administering to an animal in need thereof an effective amount of a Compound of Formula (I) or a pharmaceutically acceptable derivative thereof.

This application is a continuation of application Ser. No. 14/127,903,filed Dec. 19, 2013, now U.S. Pat. No. 9,273,043 B2, which is a nationalstage of PCT international application serial no. PCT/IB2012/001252,filed Jun. 21, 2012, which claims the benefit under 35 U.S.C. §119(e) ofprovisional application Ser. No. 61/499,989, filed Jun. 22, 2011, thecontents of all of which are incorporated herein by reference.

1. FIELD

The disclosure relates to Compounds of Formula (I), and pharmaceuticallyacceptable derivatives thereof, compositions comprising an effectiveamount of a Compound of Formula (I) and methods for treating orpreventing a condition such as pain, e.g., pain associated withosteoarthritis, osteoarthritis, UI, an ulcer, IBD, and IBS, comprisingadministering to an animal in need thereof an effective amount of aCompound of Formula (I).

2. BACKGROUND

Pain is the most common symptom for which patients seek medical adviceand treatment. Pain can be acute or chronic. While acute pain is usuallyself-limited, chronic pain persists for three months or longer and canlead to significant changes in a patient's personality, lifestyle,functional ability and overall quality of life (Foley, “Pain,” in CecilTextbook of Medicine, pp. 100-107 (Bennett and Plum eds., 20th ed.1996)).

Moreover, chronic pain can be classified as either nociceptive orneuropathic. Nociceptive pain includes tissue injury-induced pain andinflammatory pain such as that associated with arthritis. Neuropathicpain is caused by damage to the peripheral or central nervous system andis maintained by aberrant somatosensory processing. There is a largebody of evidence relating activity at vanilloid receptors (Di Marzo etal., “Endovanilloid signaling in pain,” Current Opinion in Neurobiology12:372-379 (2002)) to pain processing.

Nociceptive pain has been traditionally managed by administeringnon-opioid analgesics, such as acetylsalicylic acid, choline magnesiumtrisalicylate, acetaminophen, ibuprofen, fenoprofen, diflusinal, andnaproxen; or opioid analgesics, including morphine, hydromorphone,methadone, levorphanol, fentanyl, oxycodone, and oxymorphone. Id. Inaddition to the above-listed treatments, neuropathic pain, which can bedifficult to treat, has also been treated with anti-epileptics (e.g.,gabapentin, carbamazepine, valproic acid, topiramate, phenytoin), NMDAantagonists (e.g., ketamine, dextromethorphan), topical lidocaine (forpost-herpetic neuralgia), and tricyclic antidepressants (e.g.,fluoxetine, sertraline and amitriptyline).

UI is uncontrollable urination, generally caused bybladder-detrusor-muscle instability. UI affects people of all ages andlevels of physical health, both in health care settings and in thecommunity at large. Physiologic bladder contraction results in largepart from acetylcholine-induced stimulation of post-ganglionicmuscarinic-receptor sites on bladder smooth muscle. Treatments for UIinclude the administration of drugs having bladder-relaxant properties,which help to control bladder-detrusor-muscle overactivity.

None of the existing commercial drug treatments for UI has achievedcomplete success in all classes of UI patients, nor has treatmentoccurred without significant adverse side effects.

Treatment of ulcers often involves reducing or inhibiting the aggressivefactors. For example, antacids such as aluminum hydroxide, magnesiumhydroxide, sodium bicarbonate, and calcium bicarbonate can be used toneutralize stomach acids. Antacids, however, can cause alkalosis,leading to nausea, headache, and weakness. Antacids can also interferewith the absorption of other drugs into the blood stream and causediarrhea.

H₂ antagonists, such as cimetidine, ranitidine, famotidine, andnizatidine, are also used to treat ulcers. H₂ antagonists promote ulcerhealing by reducing gastric acid and digestive-enzyme secretion elicitedby histamine and other H₂ agonists in the stomach and duodenum. H₂antagonists, however, can cause breast enlargement and impotence in men,mental changes (especially in the elderly), headache, dizziness, nausea,myalgia, diarrhea, rash, and fever.

H⁺, K⁺-ATPase inhibitors such as omeprazole and lansoprazole are alsoused to treat ulcers. H⁺, K⁺-ATPase inhibitors inhibit the production ofenzymes used by the stomach to secrete acid. Side effects associatedwith H⁺, K⁺-ATPase inhibitors include nausea, diarrhea, abdominal colic,headache, dizziness, somnolence, skin rashes, and transient elevationsof plasma activities of aminotransferases.

Inflammatory-bowel disease (“IBD”) is a chronic disorder in which thebowel becomes inflamed, often causing recurring abdominal cramps anddiarrhea. The two types of IBD are Crohn's disease and ulcerativecolitis.

Crohn's disease, which can include regional enteritis, granulomatousileitis, and ileocolitis, is a chronic inflammation of the intestinalwall. Crohn's disease occurs equally in both sexes and is more common inJews of eastern-European ancestry. Most cases of Crohn's disease beginbefore age 30 and the majority start between the ages of 14 and 24. Thedisease often affects the full thickness of the intestinal wall.Generally the disease affects the lowest portion of the small intestine(ileum) and the large intestine, but can occur in any part of thedigestive tract.

Cramps and diarrhea, side effects associated with Crohn's disease, canbe relieved by anticholinergic drugs, diphenoxylate, loperamide,deodorized opium tincture, or codeine.

When Crohn's disease causes the intestine to be obstructed or whenabscesses or fistulas do not heal, surgery can be necessary to removediseased sections of the intestine. Surgery, however, does not cure thedisease, and inflammation tends to recur where the intestine isrejoined. In almost half of the cases a second operation is needed.Berkow et al., eds., “Crohn's Disease,” Merck Manual of MedicalInformation, pp. 528-530 (1997).

Ulcerative colitis is a chronic disease in which the large intestinebecomes inflamed and ulcerated, leading to episodes of bloody diarrhea,abdominal cramps, and fever. Ulcerative colitis usually begins betweenages 15 and 30; however, a small group of people have their first attackbetween ages 50 and 70. Unlike Crohn's disease, ulcerative colitis neveraffects the small intestine and does not affect the full thickness ofthe intestine. The disease usually begins in the rectum and the sigmoidcolon and eventually spreads partially or completely throughout thelarge intestine. The cause of ulcerative colitis is unknown.

Treatment of ulcerative colitis is directed to controlling inflammation,reducing symptoms, and replacing lost fluids and nutrients.Anticholinergic drugs and low doses of diphenoxylate or loperamide areadministered for treating mild diarrhea. For more intense diarrheahigher doses of diphenoxylate or loperamide, or deodorized opiumtincture or codeine are administered.

Irritable-bowel syndrome (“IBS”) is a disorder of motility of the entiregastrointestinal tract, causing abdominal pain, constipation, and/ordiarrhea. IBS affects three-times more women than men. In IBS, stimulisuch as stress, diet, drugs, hormones, or irritants can cause thegastrointestinal tract to contract abnormally. During an episode of IBS,contractions of the gastrointestinal tract become stronger and morefrequent, resulting in the rapid transit of food and feces through thesmall intestine, often leading to diarrhea. Cramps result from thestrong contractions of the large intestine and increased sensitivity ofpain receptors in the large intestine.

Treatment of IBS often involves modification of an IBS-patient's diet.Often it is recommended that an IBS patient avoid beans, cabbage,sorbitol, and fructose. A low-fat, high-fiber diet can also help someIBS patients. Regular physical activity can also help keep thegastrointestinal tract functioning properly. Drugs such as propanthelinethat slow the function of the gastrointestinal tract are generally noteffective for treating IBS. Antidiarrheal drugs, such as diphenoxylateand loperamide, help with diarrhea. Berkow et al., eds., “IrritableBowel Syndrome,” Merck Manual of Medical Information, pp. 525-526(1997).

International publication no. WO 98/31677 describes a class of aromaticamines derived from cyclic amines that are useful as antidepressantdrugs. International publication no. WO 01/027107 describes a class ofheterocyclic compounds that are sodium/proton exchange inhibitors.International publication no. WO 99/37304 describes substitutedoxoazaheterocyclic compounds useful for inhibiting factor Xa. U.S. Pat.No. 6,248,756 to Anthony et al. and international publication no. WO97/38665 describe a class of piperidine-containing compounds thatinhibit farnesyl-protein transferase (Ftase). International publicationno. WO 98/31669 describes a class of aromatic amines derived from cyclicamines useful as antidepressant drugs. International publication no. WO97/28140 describes a class of piperidines derived from1-(piperazin-1-yl)aryl(oxy/amino)carbonyl-4-aryl-piperidine that areuseful as 5-HT_(IDb) receptor antagonists. International publication no.WO 97/38665 describes a class of piperidine containing compounds thatare useful as inhibitors of farnesyl-protein transferase.

U.S. Pat. No. 4,797,419 to Moos et al. describes a class of ureacompounds for stimulating the release of acetylcholine and useful fortreating symptoms of senile cognitive decline. U.S. Pat. No. 5,891,889to Anthony et al. describes a class of substituted piperidine compoundsthat are useful as inhibitors of farnesyl-protein transferase, and thefarnesylation of the oncogene protein Ras. U.S. Pat. No. 6,150,129 toCook et al. describes a class of dinitrogen heterocycles useful asantibiotics. U.S. Pat. No. 5,529,998 to Habich et al. describes a classof benzooxazolyl- and benzothiazolyloxazolidones useful asantibacterials.

International publication no. WO 01/57008 describes a class of2-benzothiazolyl urea derivatives useful as inhibitors ofserine/threonine and tyrosine kinases. International publication no. WO02/08221 describes aryl piperazine compounds useful for treating chronicand acute pain conditions, itch, and urinary incontinence. Internationalpublication no. WO 00/59510 describes aminopyrimidines useful assorbitol dehydrogenase inhibitors.

Japanese patent application no. 11-199573 to Kiyoshi et al. describesbenzothiazole derivatives that are neuronal 5HT3 receptor agonists inthe intestinal canal nervous system and useful for treating digestivedisorders and pancreatic insufficiency. German patent application no 19934 799 to Rainer et al. describes a chiral-smectic liquid crystalmixture containing compounds with 2 linked (hetero)aromatic rings orcompounds with 3 linked (hetero)aromatic rings.

Chu-Moyer et al., J. Med. Chem. 45:511-528 (2002) describesheterocycle-substituted piperazino-pyrimidines useful as sorbitoldehydrogenase inhibitors. Khadse et al., Bull. Haff. Instt. 1(3):27-32(1975) describes 2-(N⁴-substituted-N¹-piperazinyl)pyrido(3,2-d)thiazoles and5-nitro-2-(N⁴-substituted-N¹-piperazinyl)benzthiazoles useful asanthelmintic agents.

U.S. Patent Application Publication No. US 2004/0186111 A1 andInternational publication no. WO 2004/058754 A1 describe a class ofcompounds that are useful for treating pain. U.S. Patent ApplicationPublication No. US 2006/0199824 A1 and International publication no. WO2005/009987 A1 describe a class of compounds that are useful fortreating pain. U.S. Patent Application Publication No. US 2006/0128717A1 and International publication no. WO 2005/009988 A1 describe a classof compounds that are useful for treating pain. U.S. Patent ApplicationPublication Nos. US 2009/0170867 A1, US 2009/0170868 A1, and2009/0176796 A1 and International publication no. WO 2008/132600 A2describe a class of compounds that are useful for treating pain.

There remains, however, a clear need in the art for new drugs useful fortreating or preventing pain, e.g., pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, and IBS. Citation of any reference inSection 2 of this application is not to be construed as an admissionthat such reference is prior art to the present application.

3. SUMMARY

In a first aspect of the disclosure, new compounds that exhibit affinityfor the TRPV1 receptor are described.

In some embodiments, such new compounds exhibit antagonist activity atthe TRPV1 receptor. In other embodiments, such new compounds exhibitpartial antagonist activity at the TRPV1 receptor.

Certain new compounds of the disclosure can be used to treat an animalsuffering from pain, e.g., chronic or acute pain.

In another aspect of the disclosure, methods of treating chronic oracute pain in an animal by administering one or more Compounds ofFormula (I) to an animal in need of such treatment are described. Incertain embodiments, such new Compounds of Formula (I) effectively treatchronic or acute pain in the animal, while producing fewer or reducedside effects compared to previously available compounds.

Compounds of Formula (I) are herein disclosed:

or a pharmaceutically acceptable derivative thereof, where:

R₁ is -halo or —CF₃;

R₄ is —H or —CH₃;

each R₈ and R₉ is independently —H, -halo, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OR₁₀;

R₁₀ is —(C₁-C₄)alkyl;

each halo is independently —F, —Cl, —Br, or —I; and

m is the integer 0 or 1;

(1) provided that if R₄ is —H then m is 1; and

(2) provided that if R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration, then the methyl group bondedto the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, ora (R)-3-methyl group.

In another embodiment in connection with a Compound of Formula (I), itis further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and/or

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-3-methyl group or a (R)-3-methyl group.

Compounds of Formula (I) are potent at TRPV1 receptors, and are solublein aqueous solutions at either pH 6.8 or pH 1.2.

A Compound of Formula (I), or a pharmaceutically acceptable derivativethereof, is useful for treating or preventing pain, e.g., painassociated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, orIBS (each being a “Condition”) in an animal.

The disclosure also relates to compositions comprising an effectiveamount of a Compound of Formula (I), or a pharmaceutically acceptablederivative thereof, and a pharmaceutically acceptable carrier orexcipient. The compositions are useful for treating or preventing aCondition in an animal.

The disclosure further relates to methods for treating a Conditioncomprising administering to an animal in need thereof an effectiveamount of a Compound of Formula (I), or a pharmaceutically acceptablederivative thereof.

The disclosure further relates to a Compound of Formula (I), apharmaceutically acceptable derivative thereof, a composition containinga Compound of Formula (I), and/or a composition containing apharmaceutically acceptable derivative of a Compound of Formula (I) foruse in the treatment of pain, e.g., pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal.

The disclosure further relates to use of a Compound of Formula (I), or apharmaceutically acceptable derivative thereof, in the manufacture of amedicament for treating and/or preventing a Condition, such as painand/or osteoarthritis. The disclosure further relates to a Compound ofFormula (I), or a pharmaceutically acceptable derivative thereof, foruse in the treatment and/or prevention of a Condition, such as painand/or osteoarthritis.

The disclosure further relates to methods for preventing a Conditioncomprising administering to an animal in need thereof an effectiveamount of a Compound of Formula (I), or a pharmaceutically acceptablederivative thereof.

The disclosure still further relates to methods for inhibiting TransientReceptor Potential Vanilloid 1 (“TRPV1,” formerly known as VanilloidReceptor 1 or VR1) function in a cell, comprising contacting a cellcapable of expressing TRPV1 with an effective amount of a Compound ofFormula (I), or a pharmaceutically acceptable derivative thereof.

The disclosure still further relates to a method for preparing acomposition comprising the step of admixing a Compound of Formula (I),or a pharmaceutically acceptable derivative thereof, and apharmaceutically acceptable carrier or excipient.

The disclosure still further relates to a kit comprising a containercontaining an effective amount of a Compound of Formula (I), or apharmaceutically acceptable derivative thereof.

In one embodiment, preferred Compounds of Formula (I) are Compounds ofFormula (II):

or a pharmaceutically acceptable derivative thereof, where:

R₄ is —H or —CH₃;

R₈ is —H, —F, or —CH₃;

R₉ is —H, -halo, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or—C(O)OCH₂CH₃; and

each halo is independently —F, —Cl, —Br, or —I;

(1) provided that if R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration, then the methyl group bondedto the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, ora (R)-3-methyl group.

In another embodiment in connection with a Compound of Formula (II), itis further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and/or

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-3-methyl group or a (R)-3-methyl group.

Many Compounds of Formula (II) are soluble, in some cases highlysoluble, in aqueous solutions at either pH 6.8 or pH 1.2, are potent atTRPV1 receptors, are orally bioavailable, have a good therapeutic index,and are believed to be highly efficacious in animals for the treatmentof pain and/or osteoarthritis. Moreover, Compounds of Formula (II) arecapable of ameliorating undesirable side effects, such as an increase inbody temperature that can occur upon in vivo administration of somecompounds which modulate the TRPV1 receptor.

The disclosure can be understood more fully by reference to thefollowing detailed description and illustrative examples, which areintended to exemplify non-limiting embodiments of the disclosure.

3.1. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the PXRD pattern (CuKα radiation) of the product preparedwith Compound A155(a) and fumaric acid.

FIG. 2 depicts ¹⁵N NMR CP/MAS spectra of the product prepared withCompound A155(a) and fumaric acid (leftmost), the dihydrochloride-saltof Compound A155(a) (center) and the free base of Compound A155(a)(rightmost).

FIG. 3 depicts the ¹³C NMR CP/MAS spectrum of the product prepared withCompound A155(a) and fumaric acid.

4. DETAILED DESCRIPTION

The invention includes the following:

(1.) A Compound of Formula (I):

or a pharmaceutically acceptable derivative thereof, wherein:

R₁ is -halo or —CF₃;

R₄ is —H or —CH₃;

each R₈ and R₉ is independently —H, -halo, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OR₁₀;

R₁₀ is —(C₁-C₄)alkyl;

each halo is independently —F, —Br, or —I; and

m is the integer 0 or 1;

-   -   (1) provided that if R₄ is —H then m is 1; and    -   (2) provided that if R₄ is —H and the carbon atom at the a        position of the a-b bond is in the (S) configuration, then the        methyl group bonded to the piperazine ring is a (S)-2-methyl        group, a (S)-3-methyl group, or a (R)-3-methyl group.

(2.) The compound of the above (1.) or a pharmaceutically acceptablederivative thereof, wherein it is further provided that:

-   -   (3) if R₄ is —H, the carbon atom at the a position of the a-b        bond is in the (S) configuration, R₈ is —H, and R₉ is -halo,        then the methyl group bonded to the piperazine ring is a        (R)-3-methyl group;    -   (4) if R₄ is —H, the carbon atom at the a position of the a-b        bond is in the (S) configuration, R₈ is —F, and R₉ is —F, then        the methyl group bonded to the piperazine ring is a (S)-2-methyl        group or a (S)-3-methyl group; and/or    -   (5) if R₄ is —CH₃, the carbon atoms at the a and c positions of        the a-b bond and the c-d bond are each in the (S) configuration,        R₈ is —H, R₉ is -halo, and m is 1, then the methyl group bonded        to the piperazine ring is a (S)-3-methyl group or a (R)-3-methyl        group.

(3.) The compound of the above (1.) or (2.) or a pharmaceuticallyacceptable derivative thereof, wherein R₁ is —F, —Cl, or —CF₃.

(4.) The compound of any one of the above (1.) to (3.) or apharmaceutically acceptable derivative thereof, wherein R₁ is —F.

(5.) The compound of any one of the above (1.) to (4.) or apharmaceutically acceptable derivative thereof, wherein R₁₀ is —CH₃ or—CH₂CH₃.

(6.) The compound of any one of the above (1.) to (5.) or apharmaceutically acceptable derivative thereof, wherein R₁₀ is —CH₂CH₃.

(7.) The compound of any one of the above (1.) to (6.) or apharmaceutically acceptable derivative thereof, wherein R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

(8.) The compound of any one of the above (1.) to (7.) or apharmaceutically acceptable derivative thereof, wherein R₈ is —H, —F, or—CH₃.

(9.) The compound of any one of the above (1.) to (8.) or apharmaceutically acceptable derivative thereof, wherein R₈ is —F or—CH₃.

(10.) The compound of any one of the above (1.) to (9.) or apharmaceutically acceptable derivative thereof, wherein R₉ is —H.

(11.) The compound of any one of the above (1.) to (10.) or apharmaceutically acceptable derivative thereof, wherein R₄ is —CH₃ andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (S) configuration.

(12.) The compound of any one of the above (1.) to (10.) or apharmaceutically acceptable derivative thereof, wherein R₄ is —CH₃ andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (R) configuration.

(13.) The compound of any one of the above (1.) to (10.) or apharmaceutically acceptable derivative thereof, wherein R₄ is —H and thecarbon atom at the a position of the a-b bond is in the (S)configuration.

(14.) The compound of any one of the above (1.) to (10.) or apharmaceutically acceptable derivative thereof, wherein R₄ is —H and thecarbon atom at the a position of the a-b bond is in the (R)configuration.

(15.) The compound of any one of the above (1.) to (14.) or apharmaceutically acceptable derivative thereof, wherein m is 1 and themethyl group bonded to the piperazine ring is a (S)-2-methyl group.

(16.) The compound of the above (1.) to (15.), wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, radiolabeled form, a co-crystal, or a combination thereof.

(17.) The compound of the above (15.) or (16.), wherein thepharmaceutically acceptable derivative is a hydrochloride salt, a sodiumsalt, a potassium salt, a p-toluenesulfonic acid salt, a fumaricacid-salt, or a fumarate co-crystal.

(18.) The compound of any one of the above (15.) to (16.), wherein thepharmaceutically acceptable derivative is a fumaric acid-salt, afumarate co-crystal, or a combination thereof.

(19.) The compound of any one of the above (1.) to (12.) or apharmaceutically acceptable derivative thereof, wherein m is 0.

(20.) The compound of the above (19.), wherein the pharmaceuticallyacceptable derivative is a pharmaceutically acceptable salt,radiolabeled form, or a hydrochlorate, tartrate, benzenesulfonate,p-toluenesulfonate, or fumarate co-crystal.

(21.) The compound of the above (19.) or (20.), wherein thepharmaceutically acceptable derivative is a hydrochloride salt, a sodiumsalt, a potassium salt, a p-toluenesulfonic acid salt, a fumaricacid-salt, or a fumarate co-crystal.

(22.) The compound of the above (19.), wherein the pharmaceuticallyacceptable derivative is a fumaric acid-salt, a fumarate co-crystal, ora combination thereof.

(23.) The compound of any one of the above (1.) to (8.), (11.), or (19.)or a pharmaceutically acceptable derivative thereof, which is

(24.) The compound of any one of the above (1.) to (3.), (5.) to (8.),(11.), or (19.) or a pharmaceutically acceptable derivative thereof,which is

(25.) The compound of any one of the above (1.) to (8.), (11.), or (19.)or a pharmaceutically acceptable derivative thereof, which is

(26.) The compound of any one of the above (1.) to (9.), (11.), or (19.)or a pharmaceutically acceptable derivative thereof, which is

(27.) The compound of any one of the above (23.) to (26.), which is afree base.

(28.) The compound of any one of the above (23.) to (26.), which is afumaric acid-salt, a fumarate co-crystal, or a combination thereof.

(29.) A composition comprising the compound of any one of the above (1.)to (28.) or a pharmaceutically acceptable derivative thereof and apharmaceutically acceptable carrier or excipient.

(30.) A method for treating pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprisingadministering to an animal in need thereof, an effective amount of thecompound of any one of the above (1.) to (28.) or a pharmaceuticallyacceptable derivative thereof.

(31.) A method for treating pain, pain associated with osteoarthritis,UI, an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the compound of any oneof the above (1.) to (28.) or a pharmaceutically acceptable derivativethereof.

(32.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, orIBS in an animal, comprising administering to an animal in need thereof,an effective amount of the compound of any one of the above (1.) to(28.) or a pharmaceutically acceptable derivative thereof.

(33.) A method for treating pain, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of the compound of any one of the above (1.) to (28.)or a pharmaceutically acceptable derivative thereof.

(34.) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof the compound of any one of the above (1.) to (28.) or apharmaceutically acceptable derivative thereof.

(35.) The product of combining the compound of any one of the above (1.)to (28.) with fumaric acid, where the molar ratio in the product isabout 1:0.5 of (the Compound of Formula (I)):(fumaric acid).

(36.) A composition comprising the product of the above (35.) and apharmaceutically acceptable carrier or excipient.

(37.) A method for treating pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprisingadministering to an animal in need thereof, an effective amount of theproduct of the above (35.).

(38.) A method for treating pain, pain associated with osteoarthritis,UI, an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the product of the above(35.).

(39.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, orIBS in an animal, comprising administering to an animal in need thereof,an effective amount of the product of the above (35.).

(40.) A method for treating pain, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of the product of the above (35.).

(41.) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof the product of the above (35.).

(42.) The compound of any one of the above (1.), (4.), (6.), or (8.),which is a compound of formula (II):

or a pharmaceutically acceptable derivative thereof; wherein:

R₄ is —H or —CH₃;

R₈ is —H, —F, or —CH₃;

R₉ is —H, -halo, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or—C(O)OCH₂CH₃; and

each halo is independently —F, —Cl, —Br, or —I;

-   -   (1) provided that if R₄ is —H and the carbon atom at the a        position of the a-b bond is in the (S) configuration, then the        methyl group bonded to the piperazine ring is a (S)-2-methyl        group, a (S)-3-methyl group, or a (R)-3-methyl group.

(43.) The compound of the above (42.) or a pharmaceutically acceptablederivative thereof, wherein it is further provided that:

-   -   (2) if R₄ is —H, the carbon atom at the a position of the a-b        bond is in the (S) configuration, R₈ is —H, and R₉ is -halo,        then the methyl group bonded to the piperazine ring is a        (R)-3-methyl group;    -   (3) if R₄ is —H, the carbon atom at the a position of the a-b        bond is in the (S) configuration, R₈ is —F, and R₉ is —F, then        the methyl group bonded to the piperazine ring is a (S)-2-methyl        group or a (S)-3-methyl group; and/or    -   (4) if R₄ is —CH₃, the carbon atoms at the a and c positions of        the a-b bond and the c-d bond are each in the (S) configuration,        R₈ is —H, and R₉ is -halo, then the methyl group bonded to the        piperazine ring is a (S)-3-methyl group or a (R)-3-methyl group.

(44.) The compound of the above (42.) or (43.) or a pharmaceuticallyacceptable derivative thereof, wherein R₄ is —CH₃ and the carbon atomsat the a and c positions of the a-b bond and the c-d bond are each inthe (S) configuration.

(45.) The compound of the above (42.) or (43.) or a pharmaceuticallyacceptable derivative thereof, wherein R₄ is —CH₃ and the carbon atomsat the a and c positions of the a-b bond and the c-d bond are each inthe (R) configuration.

(46.) The compound of the above (42.) or (43.) or a pharmaceuticallyacceptable derivative thereof, wherein R₄ is —H and the carbon atom atthe a position of the a-b bond is in the (S) configuration.

(47.) The compound of the above (42.) or (43.) or a pharmaceuticallyacceptable derivative thereof, wherein R₄ is —H and the carbon atom atthe a position of the a-b bond is in the (R) configuration.

(48.) The compound of any one of the above (42.) to (47.) or apharmaceutically acceptable derivative thereof, wherein the methyl groupbonded to the piperazine ring is a (S)-3-methyl group.

(49.) The compound of the above (48.) or a pharmaceutically acceptablederivative thereof, wherein R₉ is —H.

(50.) The compound of the above (48.) or (49.) or a pharmaceuticallyacceptable derivative thereof, wherein R₈ is —F.

(51.) The compound of any one of the above (48.) to (50.), wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, or a fumarate co-crystal.

(52.) The compound of any one of the above (48.) to (51.), wherein thepharmaceutically acceptable derivative is a hydrochloride salt, a sodiumsalt, a potassium salt, a p-toluenesulfonic acid salt, a fumaricacid-salt, or a fumarate co-crystal.

(53.) The compound of any one of the above (48.) to (50.), wherein thepharmaceutically acceptable derivative is a fumaric acid-salt, afumarate co-crystal, or a combination thereof.

(54.) The compound of any one of the above (42.) to (47.) or apharmaceutically acceptable derivative thereof, wherein the methyl groupbonded to the piperazine ring is a (S)-2-methyl group.

(55.) The compound of the above (54.) or a pharmaceutically acceptablederivative thereof, wherein R₉ is —H.

(56.) The compound of the above (54.) or (55.) or a pharmaceuticallyacceptable derivative thereof, wherein R₈ is —F.

(57.) The compound of any one of the above (54.) to (56.), wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, or a fumarate co-crystal.

(58.) The compound of any one of the above (54.) to (57.), wherein thepharmaceutically acceptable derivative is a hydrochloride salt, a sodiumsalt, a potassium salt, a p-toluenesulfonic acid salt, a fumaricacid-salt, or a fumarate co-crystal.

(59.) The compound of any one of the above (54.) to (56.), wherein thepharmaceutically acceptable derivative is a fumaric acid-salt, afumarate co-crystal, or a combination thereof.

(60.) The compound of any one of the above (42.) to (47.) or apharmaceutically acceptable derivative thereof, wherein the methyl groupbonded to the piperazine ring is a (R)-3-methyl group.

(61.) The compound of the above (60.) or a pharmaceutically acceptablederivative thereof, wherein R₉ is —H.

(62.) The compound of the above (60.) or (61.) or a pharmaceuticallyacceptable derivative thereof, wherein R₈ is —F.

(63.) The compound of any one of the above (60.) to (62.), wherein thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, or a fumarate co-crystal.

(64.) The compound of any one of the above (60.) to (63.), wherein thepharmaceutically acceptable derivative is a hydrochloride salt, a sodiumsalt, a potassium salt, a p-toluenesulfonic acid salt, a fumaricacid-salt, or a fumarate co-crystal.

(65.) The compound of any one of the above (60.) to (62.), wherein thepharmaceutically acceptable derivative is a fumaric acid-salt, afumarate co-crystal, or a combination thereof.

(66.) The compound of any one of the above (42.), (43.), (46.), (54.),(55.), or (57.) to (59.) or a pharmaceutically acceptable derivativethereof, which is

(67.) The compound of any one of the above (42.) to (44.), (60.), or(62.) to (65.) or a pharmaceutically acceptable derivative thereof,which is

(68.) The compound of any one of the above (42.), (43.), (47.), or (54.)to (59.) or a pharmaceutically acceptable derivative thereof, which is

(69.) The compound of any one of the above (42.), (43.), (46.), or (54.)to (59.) or a pharmaceutically acceptable derivative thereof, which is

(70.) The compound of any one of the above (42.), (43.), (46.), (54.),or (57.) to (59.) or a pharmaceutically acceptable derivative thereof,which is

(71.) The compound of any one of the above (42.), (43.), or (47) or apharmaceutically acceptable derivative thereof, which is

(72.) The compound of any one of the above (42.), (43.), (46.), (54.),or (56.) to (59.) or a pharmaceutically acceptable derivative thereof,which is

(73.) The compound of any one of the above (42.), (43.), (46.), (60.),or (63.) to (65.) or a pharmaceutically acceptable derivative thereof,which is

(74.) The compound of any one of the above (66.) to (73.), which is afree base.

(75.) The compound of any one of the above (66.) to (73.), which is afumaric acid-salt, a fumarate co-crystal, or a combination thereof.

(76.) A composition comprising the compound of any one of the above(42.) to (75.) or a pharmaceutically acceptable derivative thereof and apharmaceutically acceptable carrier or excipient.

(77.) A method for treating pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprisingadministering to an animal in need thereof, an effective amount of thecompound of any one of the above (42.) to (75.) or a pharmaceuticallyacceptable derivative thereof.

(78.) A method for treating pain, pain associated with osteoarthritis,UI, an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the compound of any oneof the above (42.) to (75.) or a pharmaceutically acceptable derivativethereof.

(79.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, orIBS in an animal, comprising administering to an animal in need thereof,an effective amount of the compound of any one of the above (42.) to(75.) or a pharmaceutically acceptable derivative thereof.

(80.) A method for treating pain, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of the compound of any one of the above (42.) to (75.)or a pharmaceutically acceptable derivative thereof.

(81.) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof the compound of any one of the above (42.) to (75.) or apharmaceutically acceptable derivative thereof.

(82.) The product of combining the compound of any one of the above(42.) to (74.) with fumaric acid, where the molar ratio in the productis about 1:0.5 of (the Compound of Formula (I)):(fumaric acid).

(83.) A composition comprising the product of the above (82.) and apharmaceutically acceptable carrier or excipient.

(84.) A method for treating pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprisingadministering to an animal in need thereof, an effective amount of theproduct of the above (82.).

(85.) A method for treating pain, pain associated with osteoarthritis,UI, an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the product of the above(82.).

(86.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, orIBS in an animal, comprising administering to an animal in need thereof,an effective amount of the product of the above (82.).

(87.) A method for treating pain, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of the product of the above (82.).

(88.) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof the product of the above (82.).

(89.) A compound which is

or a pharmaceutically acceptable derivative thereof.

(90.) A composition comprising the compound of the above (89.) or apharmaceutically acceptable derivative thereof and a pharmaceuticallyacceptable carrier or excipient.

(91.) A method for treating pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal, comprisingadministering to an animal in need thereof, an effective amount of thecompound of the above (89.) or a pharmaceutically acceptable derivativethereof.

(92.) A method for treating pain, pain associated with osteoarthritis,UI, an ulcer, IBD, or IBS in an animal, comprising administering to ananimal in need thereof, an effective amount of the compound of the above(89.) or a pharmaceutically acceptable derivative thereof.

(93.) A method for treating pain, osteoarthritis, UI, an ulcer, IBD, orIBS in an animal, comprising administering to an animal in need thereof,an effective amount of the compound of the above (89.) or apharmaceutically acceptable derivative thereof.

(94.) A method for treating pain, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of the compound of the above (89.) or apharmaceutically acceptable derivative thereof.

(95.) A method of inhibiting TRPV1 function in a cell comprisingcontacting a cell capable of expressing TRPV1 with an effective amountof the compound of the above (89.) or a pharmaceutically acceptablederivative thereof.

(96.) The compound of any one of the above (1.) to (95.) or apharmaceutically acceptable derivative thereof, wherein the % ee of thecompound is at least about 90%.

(97.) The compound of any one of the above (1.) to (96.) or apharmaceutically acceptable derivative thereof, wherein the % ee of thecompound is at least about 93%.

(98.) A compound, product or a pharmaceutically acceptable derivativethereof or composition of any one of the above (1.) to (29.), (35.),(36.), (42.) to (76.), (82.), (83.), (89.), (90.), (96.), or (97.) foruse in the treatment of pain, pain associated with osteoarthritis,osteoarthritis, UI, an ulcer, IBD, or IBS in an animal.

(99.) A compound, product or a pharmaceutically acceptable derivativethereof or composition of any one of the above (1.) to (29.), (35.),(36.), (42.) to (76.), (82.), (83.), (89.), (90.), or (96.) to (98.) foruse in the treatment of pain in an animal.

(100.) A compound, product or composition of any one of the above (1.)to (29.), (35.), (36.), (42.) to (76.), (82.), (83.), (89.), (90.), or(96.) to (98.) for use in the treatment of pain associated withosteoarthritis in an animal.

(101.) A compound, product or a pharmaceutically acceptable derivativethereof or composition of any one of the above (1.) to (29.), (35.),(36.), (42.) to (76.), (82.), (83.), (89.), (90.), or (96.) to (98.) foruse in the treatment of osteoarthritis in an animal.

(102.) Use of a compound, product or composition of any one of the above(1.) to (29.), (35.), (36.), (42.) to (76.), (82.), (83.), (89.), (90.),or (96.) to (98.) or a pharmaceutically acceptable derivative thereof inthe manufacture of a medicament for the treatment of pain, painassociated with osteoarthritis, osteoarthritis, UI, an ulcer, IBD, orIBS

4.1 Compounds of Formula (I)

The disclosure encompasses Compounds of Formula (I):

or a pharmaceutically acceptable derivative thereof,

(1) provided that if R₄ is —H then m is 1, and

(2) provided that if R₄ is —H and the a-b bond is in the (S)configuration, then the methyl group bonded to the piperazine ring is a(S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group,

where R₁, R₄, R₈, R₉, and m are as defined above for Compounds ofFormula (I).

Certain embodiments of formula (I) are presented below.

In one embodiment, a Compound of Formula (I) is a free base.

In another embodiment, a Compound of Formula (I) is a pharmaceuticallyacceptable derivative of a Compound of Formula (I).

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (I) is a pharmaceutically acceptable salt. Inanother embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (I) is a fumaric acid-salt. In another embodiment,the pharmaceutically acceptable derivative of a Compound of Formula (I)is a fumaric acid-salt where the molar ratio of the Compound of Formula(I):fumaric acid is about 1:0.5.

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (I) is a co-crystal. In another embodiment, thepharmaceutically acceptable derivative of a Compound of Formula (I) is afumarate co-crystal. In another embodiment, the pharmaceuticallyacceptable derivative of a Compound of Formula (I) is a fumarateco-crystal where the molar ratio of the Compound of Formula (I):fumarateis about 1:0.5.

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (I) is a fumaric acid-salt, a fumarate co-crystal,or a combination thereof. In another embodiment, the molar ratio of theCompound of Formula (I):(fumaric acid and/or fumarate) is about I:0.5.

Other embodiments relate to the product of combining a Compound ofFormula (I) with fumaric acid, where the molar ratio in the product isabout 1:0.5 of (the Compound of Formula (I)):(fumaric acid); acomposition comprising that product and a pharmaceutically acceptablecarrier or excipient; a method for treating pain, e.g., pain associatedwith osteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of that product; and a method of inhibiting TRPV1function in a cell comprising contacting a cell capable of expressingTRPV1 with an effective amount of that product.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group.

In another embodiment, it is further provided that:

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup.

In another embodiment, it is further provided that:

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and (4) if R₄ is—H, the carbon atom at the a position of the a-b bond is in the (S)configuration, R₈ is —F, and R₉ is —F, then the methyl group bonded tothe piperazine ring is a (S)-2-methyl group or a (S)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(4) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(5) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, R₉ is-halo, and m is 1, then the methyl group bonded to the piperazine ringis a (S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, R₁ is —F, —Cl, —Br, or —CF₃.

In another embodiment, R₁ is —F, —Cl, or —CF₃.

In another embodiment, R₁ is —F or —CF₃.

In another embodiment, R₁ is —Cl or —CF₃.

In another embodiment, R₁ is —F or —Cl.

In another embodiment, R₁ is —F.

In another embodiment, R₁ is —Cl.

In another embodiment, R₁ is —CF₃.

In another embodiment, R₁ is —Br.

In another embodiment, R₁₀ is —CH₃ or —CH₂CH₃.

In another embodiment, R₁₀ is —CH₂CH₃.

In another embodiment, R₁₀ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃.

In another embodiment, R₉ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃.

In another embodiment, R₉ is —H, —F, or —Cl.

In another embodiment, R₉ is —H or —F.

In another embodiment, R₉ is —H or —Cl.

In another embodiment, R₉ is —H or —CH₃.

In another embodiment, R₉ is —F or —CH₃.

In another embodiment, R₉ is —F or —Cl.

In another embodiment, R₉ is —Cl or —CH₃.

In another embodiment, R₉ is —H.

In another embodiment, R₉ is —F.

In another embodiment, R₉ is —Cl.

In another embodiment, R₉ is —CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, or —OCF₃.

In another embodiment, R₈ is —H, —F, —Cl, —CH₃, or —OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, or —CH₃.

In another embodiment, R₈ is —H, —F, —Cl, or —OCH₃.

In another embodiment, R₈ is —H, —F, —Cl, or —OCF₃.

In another embodiment, R₈ is —H, —F, or —CH₃.

In another embodiment, R₈ is —H, —F, or —OCH₃.

In another embodiment, R₈ is —H, —F, or —OCF₃.

In another embodiment, R₈ is —H, —F, or —Cl.

In another embodiment, R₈ is —H or —F.

In another embodiment, R₈ is —H or —Cl.

In another embodiment, R₈ is —H or —CH₃.

In another embodiment, R₈ is —F or —CH₃.

In another embodiment, R₈ is —F or —Cl.

In another embodiment, R₈ is —Cl or —CH₃.

In another embodiment, R₈ is —H.

In another embodiment, R₈ is —F.

In another embodiment, R₈ is —Cl.

In another embodiment, R₈ is —CH₃.

In another embodiment, R₈ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —H, —F, or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —H, —F, or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —H,—F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —H,—F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —H, —F, or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —H, —F, or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —H, —F, or—CH₃.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H or —F and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H or —Cl and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —F or —Cl and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —F and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —Cl and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —CH₃ and R₈ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —F or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —F or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —F and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F and R₈ is —F or —CH₃.

In another embodiment, R₉ is —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —F.

In another embodiment, R₉ is —H or —F and R₈ is —F.

In another embodiment, R₉ is —H or —Cl and R₈ is —F.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —F or —Cl and R₈ is —F.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H and R₈ is —F.

In another embodiment, R₉ is —F and R₈ is —F.

In another embodiment, R₉ is —Cl and R₈ is —F.

In another embodiment, R₉ is —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F or —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F or —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃, R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃,R₈ is —F or —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃, R₈ is —For —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃, R₈ is —For —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃, R₈ is —F or—CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃, R₈ is —F or—CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃, R₈ is —F or —CH₃, andR₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃, R₈ is —F or —CH₃,and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃, R₈ is —F or —CH₃,and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —CH₃, R₈ is —F or —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —OCH₃, R₈ is —F or —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —OCF₃, R₈ is —F or —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —Cl, R₈ is —F or —CH₃, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H or —F, R₈ is —F or —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H or —Cl, R₈ is —F or —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H or —CH₃, R₈ is —F or —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —F or —CH₃, R₈ is —F or —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —F or —Cl, R₈ is —F or —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —Cl or —CH₃, R₈ is —F or —CH₃, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —F, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —Cl, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —CH₃, R₈ is —F or —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃,R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃, R₈ is—F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃, R₈ is—F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃, R₈ is —F, andR₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃, R₈ is —F, andR₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃, R₈ is —F, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃, R₈ is —F, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃, R₈ is —F, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —CH₃, R₈ is —F, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, —F, or —OCH₃, R₈ is —F, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, or —OCF₃, R₈ is —F, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, or —Cl, R₈ is —F, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H or —F, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H or —Cl, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H or —CH₃, R₈ is —F, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —F or —CH₃, R₈ is —F, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —F or —Cl, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —Cl or —CH₃, R₈ is —F, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —F, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —Cl, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —CH₃, R₈ is —F, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —CH₃, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —CH₃, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃,R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃, R₈ is—CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃, R₈ is—CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃, R₈ is —CH₃,and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃, R₈ is —CH₃,and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃, R₈ is —CH₃, and R₁ is—Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃, R₈ is —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃, R₈ is —CH₃, and R₁is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, or —CH₃, R₈ is —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, or —OCH₃, R₈ is —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, or —OCF₃, R₈ is —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H, —F, or —Cl, R₈ is —CH₃, and R₁ is —Clor —CF₃.

In another embodiment, R₉ is —H or —F, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H or —Cl, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H or —CH₃, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —F or —CH₃, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —F or —Cl, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —Cl or —CH₃, R₈ is —CH₃, and R₁ is —Cl or—CF₃.

In another embodiment, R₉ is —H, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —F, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —Cl, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —CH₃, R₈ is —CH₃, and R₁ is —Cl or —CF₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, —C(O)OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃,R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃, R₈ is—F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃, R₈ is—F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃, R₈ is —F, andR₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃, R₈ is —F, andR₁ is —Cl.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃, R₈ is —F, and R₁ is—Cl.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃, R₈ is —F, and R₁ is—Cl.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃, R₈ is —F, and R₁ is—Cl.

In another embodiment, R₉ is —H, —F, or —CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, or —OCH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, or —OCF₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, —F, or —Cl, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H or —F, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H or —Cl, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H or —CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —F or —CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —F or —Cl, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —Cl or —CH₃, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —H, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —F, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —Cl, R₈ is —F, and R₁ is —Cl.

In another embodiment, R₉ is —CH₃, R₁ is —F, and R₁ is —Cl.

In another embodiment, R₄ is —H.

In another embodiment, R₄ is —CH₃.

In another embodiment, R₄ is —H and R₁ is —F, —Cl, or —CF₃.

In another embodiment, R₄ is —CH₃ and R₁ is —F, —Cl, or —CF₃.

In another embodiment, R₄ is —H and R₁ is —F or —CF₃.

In another embodiment, R₄ is —CH₃ and R₁ is —F or —CF₃.

In another embodiment, R₄ is —H and R₁ is —F or —Cl.

In another embodiment, R₄ is —CH₃ and R₁ is —F or —Cl.

In another embodiment, R₄ is —H and R₁ is —Cl or —CF₃.

In another embodiment, R₄ is —CH₃ and R₁ is —Cl or —CF₃.

In another embodiment, R₄ is —CH₃ and m is 0.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃ and m is 0.

In another embodiment, R₄ is —H and m is 1.

In another embodiment, R₄ is —CH₃ and m is 1.

In another embodiment, R₄ is —H, R₁ is —F, —Cl, or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, and m is 0.

In another embodiment, R₄ is —H, R₁ is —Cl or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, and m is 0.

In another embodiment, R₄ is —H, R₁ is —F or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, and m is 0.

In another embodiment, R₄ is —H, R₁ is —F or —Cl, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, and m is 1

In another embodiment, R₄ is —CH₃, R₁ is —Cl, and m is 0.

In another embodiment, R₄ is —H, R₁ is —Cl, and m is 1.

In another embodiment, R₄ is —CH₃, R₁ is Cl, and m is 1.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, and m is 0.

In another embodiment, R₄ is —H, R₁ is —CF₃, and m is 1.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, and m is 1.

In another embodiment, R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —F, —Cl, or —CF₃, and the carbonatom at the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —F or —CF₃, and the carbon atomat the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —F or —Cl, and the carbon atom atthe a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —Cl or —CF₃, and the carbon atomat the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, m is 1, and the carbon atom at the aposition of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —F, —Cl, or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (S)configuration.

In another embodiment, R₄ is —H, R₁ is —Cl or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (S)configuration.

In another embodiment, R₄ is —H, R₁ is —F or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (S)configuration.

In another embodiment, R₄ is —H, R₁ is —F or —Cl, m is 1, and the carbonatom at the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —Cl, m is 1, and the carbon atomat the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H, R₁ is —CF₃, m is 1, and the carbon atomat the a position of the a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —F, —Cl, or —CF₃, and the carbonatom at the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —F or —CF₃, and the carbon atomat the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —F or —Cl, and the carbon atom atthe a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —Cl or —CF₃, and the carbon atomat the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, m is 1, and the carbon atom at the aposition of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —F, —Cl, or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (R)configuration.

In another embodiment, R₄ is —H, R₁ is —Cl or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (R)configuration.

In another embodiment, R₄ is —H, R₁ is —F or —CF₃, m is 1, and thecarbon atom at the a position of the a-b bond is in the (R)configuration.

In another embodiment, R₄ is —H, R₁ is —F or —Cl, m is 1, and the carbonatom at the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —Cl, m is 1, and the carbon atomat the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —H, R₁ is —CF₃, m is 1, and the carbon atomat the a position of the a-b bond is in the (R) configuration.

In another embodiment, R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, and the carbon atomsat the a and c positions of the a-b bond and the c-d bond are each inthe (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃, m is 0, and the carbon atoms at the aand c positions of the a-b bond and the c-d bond are each in the (S)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, m is 0, andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (S) configuration.

In another embodiment, R₄ is —CH₃, m is 1, and the carbon atoms at the aand c positions of the a-b bond and the c-d bond are each in the (S)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, m is 1, andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl, m is 0, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is Cl, m is 1, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, m is 0, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, m is 1, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (S) configuration.

In another embodiment, R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, and the carbon atomsat the a and c positions of the a-b bond and the c-d bond are each inthe (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, R₄ is —CH₃, m is 0, and the carbon atoms at the aand c positions of the a-b bond and the c-d bond are each in the (R)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, m is 0, andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (R) configuration.

In another embodiment, R₄ is —CH₃, m is 1, and the carbon atoms at the aand c positions of the a-b bond and the c-d bond are each in the (R)configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F, —Cl, or —CF₃, m is 1, andthe carbon atoms at the a and c positions of the a-b bond and the c-dbond are each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl or —CF₃, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —CF₃, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, m is 0, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —F or —Cl, m is 1, and thecarbon atoms at the a and c positions of the a-b bond and the c-d bondare each in the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —Cl, m is 0, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is Cl, m is 1, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, m is 0, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, R₄ is —CH₃, R₁ is —CF₃, m is 1, and the carbonatoms at the a and c positions of the a-b bond and the c-d bond are eachin the (R) configuration.

In another embodiment, m is 1 and the methyl group bonded to thepiperazine ring is a (S)-2-methyl group.

In another embodiment, m is 1 and the methyl group bonded to thepiperazine ring is a (S)-3-methyl group.

In another embodiment, m is 1 and the methyl group bonded to thepiperazine ring is a (R)-3-methyl group.

Aqueous solubility of compounds is often a desirable feature. Forexample, aqueous solubility of a compound permits that compound to bemore easily formulated into a variety of dosage forms that can beadministered to an animal. When a compound is not fully soluble inbiological fluids, e.g., blood, it can precipitate and the animal'sexposure to the drug will accordingly not correspond to the administereddose. Aqueous solubility increases the likelihood that a compound willhave higher dissolution and, for compounds with good permeability, itresults in high exposure in an animal's blood, and increases the abilityto predict exposure at the target sight of the compound.

Many Compounds of Formula (I) are soluble, and in some cases highlysoluble, in aqueous solution. For example, at either pH 6.8 or pH 1.2,compound 200 is insoluble in aqueous solution, i.e., has an aqueoussolubility <0.1 μM. In contrast, the aqueous solubility at pH 1.2 of thefollowing Compounds of Formula (I) is >50 μM: A126(a), A155(a), A155(d),A155(e), A158(a), C125(r), and C126(r). The aqueous solubility at pH6.8, in μM, of Compounds of Formula (I) A126(a), A155(a), A155(d),A155(e), A158(a), C125(r), and C126(r) is 14, 17, 4.0, 5.0, 5.0, 3.0,and 4.0, respectively. Additionally, the aqueous solubility at either pH1.2 or pH 6.8 of Compound of Formula (I) A122(a) is >50 μM. The aqueoussolubility, in μM, at pH 1.2 of compounds 209, 210, 211, 212, 213, 214,and 215 is 9.3, 2.0, 1.3, 10.3, 39.6, >50 and 9.6, respectively. Thefollowing compounds are aqueous insoluble at pH 6.8: 203, 207, 200, and208. The following compounds have low aqueous solubility at pH 6.8: 209,210, 211, 212, 213, 214, and 215 have aqueous solubility, in μM, of 1.0,0.4, 0.4, 1.9, 0.8, 1.8, and 0.6, respectively.

The following chemical structures relate to certain of theabove-discussed compounds:

4.2 Compounds of Formula (II)

Preferred Compounds of Formula (I) are Compounds of Formula (II):

or a pharmaceutically acceptable derivative thereof,

(1) provided that if R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration, then the methyl group bondedto the piperazine ring is a (S)-2-methyl group, a (S)-3-methyl group, ora (R)-3-methyl group,

where R₄, R₈, and R₉ are as defined above for Compounds of Formula (II).

Certain embodiments of formula (II) are presented below.

In one embodiment, a Compound of Formula (II) is a free base.

In another embodiment, a Compound of Formula (II) is a pharmaceuticallyacceptable derivative of a Compound of Formula (II).

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (II) is a pharmaceutically acceptable salt. Inanother embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (II) is a fumaric acid-salt. In another embodiment,the pharmaceutically acceptable derivative of a Compound of Formula (II)is a fumaric acid-salt where the molar ratio of the Compound of Formula(II):fumaric acid is about 1:0.5.

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (II) is a co-crystal. In another embodiment, thepharmaceutically acceptable derivative of a Compound of Formula (II) isa fumarate co-crystal. In another embodiment, the pharmaceuticallyacceptable derivative of a Compound of Formula (II) is a fumarateco-crystal where the molar ratio of the Compound of Formula(II):fumarate is about 1:0.5.

In another embodiment, the pharmaceutically acceptable derivative of aCompound of Formula (II) is a fumaric acid-salt, a fumarate co-crystal,or a combination thereof. In another embodiment, the molar ratio of theCompound of Formula (II):(fumaric acid and/or fumarate) is about 1:0.5.

Other embodiments relate to the product of combining a Compound ofFormula (II) with fumaric acid, where the molar ratio in the product isabout 1:0.5 of (the Compound of Formula (II)):(fumaric acid); acomposition comprising that product and a pharmaceutically acceptablecarrier or excipient; a method for treating pain, e.g., pain associatedwith osteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS in ananimal, comprising administering to an animal in need thereof, aneffective amount of that product; and a method of inhibiting TRPV1function in a cell comprising contacting a cell capable of expressingTRPV1 with an effective amount of that product.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup.

In another embodiment, it is further provided that:

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-3-methyl group or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, it is further provided that:

(2) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R₈ is —H, and R₉ is -halo, then the methyl groupbonded to the piperazine ring is a (R)-3-methyl group;

(3) if R₄ is —H, the carbon atom at the a position of the a-b bond is inthe (S) configuration, R is —F, and R₉ is —F, then the methyl groupbonded to the piperazine ring is a (S)-2-methyl group or a (S)-3-methylgroup; and

(4) if R₄ is —CH₃, the carbon atoms at the a and c positions of the a-bbond and the c-d bond are each in the (S) configuration, R₈ is —H, andR₉ is -halo, then the methyl group bonded to the piperazine ring is a(S)-2-methyl group, a (S)-3-methyl group, or a (R)-3-methyl group.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃.

In another embodiment, R₉ is —H, —F, or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃.

In another embodiment, R₉ is —H, —F, or —Cl.

In another embodiment, R₉ is —H or —F.

In another embodiment, R₉ is —H or —Cl.

In another embodiment, R₉ is —H or —CH₃.

In another embodiment, R₉ is —F or —CH₃.

In another embodiment, R₉ is —F or —Cl.

In another embodiment, R₉ is —Cl or —CH₃.

In another embodiment, R₉ is —H.

In another embodiment, R₉ is —F.

In another embodiment, R₉ is —Cl.

In another embodiment, R₉ is —CH₃.

In another embodiment, R₈ is —H or —F.

In another embodiment, R₈ is —H or —CH₃.

In another embodiment, R₈ is —F or —CH₃.

In another embodiment, R₈ is —H.

In another embodiment, R₈ is —F.

In another embodiment, R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —F or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —F or—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —F and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F or —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H and R₈ is —F or —CH₃.

In another embodiment, R₉ is —F and R₈ is —F or —CH₃.

In another embodiment, R₉ is —Cl and R₈ is —F or —CH₃.

In another embodiment, R₉ is —CH₃ and R₈ is —F or —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —F.

In another embodiment, R₉ is —H or —F and R₈ is —F.

In another embodiment, R₉ is —H or —Cl and R₈ is —F.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —F or —Cl and R₈ is —F.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H and R₈ is —F.

In another embodiment, R₉ is —F and R₈ is —F.

In another embodiment, R₉ is —Cl and R₈ is —F.

In another embodiment, R₉ is —CH₃ and R₈ is —F.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —OCH₂CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃,or —CH₂OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃,—OCH₂CH₃, or —CH₂OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—OCH₂CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, —OCF₃, or—CH₂OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃, —OCH₃, or—OCF₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, —OCH₃, or —OCF₃and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCF₃ and R₈ is—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, —CF₃, or —OCH₃ and R₈ is—CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCF₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, —CH₃, or —OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, —Cl, or —OCF₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, or —CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, or —OCH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, or —OCF₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H, —F, or —Cl and R₈ is —CH₃.

In another embodiment, R₉ is —H or —F and R₈ is —CH₃.

In another embodiment, R₉ is —H or —Cl and R₈ is —CH₃.

In another embodiment, R₉ is —H or —CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —F or —CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —F or —Cl and R₈ is —CH₃.

In another embodiment, R₉ is —Cl or —CH₃ and R₈ is —CH₃.

In another embodiment, R₉ is —H and R₈ is —CH₃.

In another embodiment, R₉ is —F and R₈ is —CH₃.

In another embodiment, R₉ is —Cl and R₈ is —CH₃.

In another embodiment, R₉ is —CH₃ and R₈ is —CH₃.

In another embodiment, R₄ is —H.

In another embodiment, R₄ is —CH₃.

In another embodiment, R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration.

In another embodiment, R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (R) configuration.

In another embodiment, R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration.

In another embodiment, R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration.

In another embodiment, the methyl group bonded to the piperazine ring isa (S)-2-methyl group.

In another embodiment, the methyl group bonded to the piperazine ring isa (S)-3-methyl group.

In another embodiment, the methyl group bonded to the piperazine ring isa (R)-3-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, and the methyl group bonded tothe piperazine ring is a (S)-2-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, and the methyl group bonded tothe piperazine ring is a (S)-2-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, and the methyl group bonded to the piperazine ring is a(S)-2-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, and the methyl group bonded to the piperazine ring is a(S)-2-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, and the methyl group bonded tothe piperazine ring is a (S)-3-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, and the methyl group bonded tothe piperazine ring is a (S)-3-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, and the methyl group bonded to the piperazine ring is a(S)-3-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, and the methyl group bonded to the piperazine ring is a(S)-3-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, and the methyl group bonded tothe piperazine ring is a (R)-3-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, and the methyl group bonded tothe piperazine ring is a (R)-3-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, and the methyl group bonded to the piperazine ring is a(R)-3-methyl group.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, and the methyl group bonded to the piperazine ring is a(R)-3-methyl group.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, and R is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, and R₈ is —F or —CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, and R₉ is —H, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, and R₉ is —H, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃,—CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —F or —CH₃, and R₉ is —H, —Cl, —Br, —CH₃,—CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl,—Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —F, and R₉ is —H, —Cl, —Br, —CH₃, —CF₃, —OCH₃,—OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-2-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-2-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (S)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(S)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (S) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —H, the carbon atom at the a position ofthe a-b bond is in the (R) configuration, the methyl group bonded to thepiperazine ring is a (R)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F,—Cl, —Br, —CH₃, —CF₃, —OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

In another embodiment, R₄ is —CH₃, the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration, the methyl group bonded to the piperazine ring is a(R)-3-methyl group, R₈ is —CH₃, and R₉ is —H, —F, —Cl, —Br, —CH₃, —CF₃,—OCH₃, —OCF₃, —OCH₂CH₃, —CH₂OCH₃, or —C(O)OCH₂CH₃.

Illustrative Compounds of Formulae (I) and/or (II) are listed below inTables 1-3.

TABLE 1 (a)

(b)

(c)

(d)

(e)

(f)

(g)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₈ R₉ A A1a, b, c, d, e, f or g —Cl —H —H A2 b, d, e, f or g —Cl —H —ClA3 b, d, e, f or g —Cl —H —Br A4 b, d, e, f or g —Cl —H —F A5 a, b, c,d, e, f or g —Cl —H —CH₃ A6 a, b, c, d, e, f or g —Cl —H —OCH₃ A7 a, b,c, d, e, f or g —Cl —H —OCH₂CH₃ A8 a, b, c, d, e, f or g —Cl —H —CF₃ A9a, b, c, d, e, f or g —Cl —H —OCF₃ A10 a, b, c, d, e, f or g —Cl —H—CH₂OCH₃ A11 a, b, c, d, e, f or g —Cl —H —C(O)OCH₂CH₃ A12 a, b, c, d,e, f or g —Cl —Cl —H A13 a, b, c, d, e, f or g —Cl —Cl —Cl A14 a, b, c,d, e, f or g —Cl —Cl —Br A15 a, b, c, d, e, f or g —Cl —Cl —F A16 a, b,c, d, e, f or g —Cl —Cl —CH₃ A17 a, b, c, d, e, f or g —Cl —Cl —OCH₃ A18a, b, c, d, e, f or g —Cl —Cl —OCH₂CH₃ A19 a, b, c, d, e, f or g —Cl —Cl—CF₃ A20 a, b, c, d, e, f or g —Cl —Cl —OCF₃ A21 a, b, c, d, e, f or g—Cl —Cl —CH₂OCH₃ A22 a, b, c, d, e, f or g —Cl —Cl —C(O)OCH₂CH₃ A23 a,b, c, d, e, f or g —Cl —Br —H A24 a, b, c, d, e, f or g —Cl —Br —Cl A25a, b, c, d, e, f or g —Cl —Br —Br A26 a, b, c, d, e, f or g —Cl —Br —FA27a, b, c, d, e, f or g —Cl —Br —CH₃ A28 a, b, c, d, e, f or g —Cl —Br—OCH₃ A29 a, b, c, d, e, f or g —Cl —Br —OCH₂CH₃ A30 a, b, c, d, e, f org —Cl —Br —CF₃ A31 a, b, c, d, e, f or g —Cl —Br —OCF₃ A32 a, b, c, d,e, f or g —Cl —Br —CH₂OCH₃ A33 a, b, c, d, e, f or g —Cl —Br—C(O)OCH₂CH₃ A34 a, b, c, d, e, f or g —Cl —F —H A35 a, b, c, d, e, f org —Cl —F —Cl A36 a, b, c, d, e, f or g —Cl —F —Br A37 a, c, d, e, f or g—Cl —F —F A38 a, b, c, d, e, f or g —Cl —F —CH₃ A39 a, b, c, d, e, f org —Cl —F —OCH₃ A40 a, b, c, d, e, f or g —Cl —F —OCH₂CH₃ A41 a, b, c, d,e, f or g —Cl —F —CF₃ A42 a, b, c, d, e, f or g —Cl —F —OCF₃ A43 a, b,c, d, e, f or g —Cl —F —CH₂OCH₃ A44 a, b, c, d, e, f or g —Cl —F—C(O)OCH₂CH₃ A45 a, b, c, d, e, f or g —Cl —CH₃ —H A46 a, b, c, d, e, for g —Cl —CH₃ —Cl A47 a, b, c, d, e, f or g —Cl —CH₃ —Br A48 a, b, c, d,e, f or g —Cl —CH₃ —F A49 a, b, c, d, e, f or g —Cl —CH₃ —CH₃ A50 a, b,c, d, e, f or g —Cl —CH₃ —OCH₃ A51 a, b, c, d, e, f or g —Cl —CH₃—OCH₂CH₃ A52 a, b, c, d, e, f or g —Cl —CH₃ —CF₃ A53a, b, c, d, e, f org —Cl —CH₃ —OCF₃ A54 a, b, c, d, e, f or g —Cl —CH₃ —CH₂OCH₃ A55 a, b,c, d, e, f or g —Cl —CH₃ —C(O)OCH₂CH₃ A56 a, b, c, d, e, f or g —Cl—OCH₃ —H A57 a, b, c, d, e, f or g —Cl —OCH₃ —Cl A58 a, b, c, d, e, f org —Cl —OCH₃ —Br A59 a, b, c, d, e, f or g —Cl —OCH₃ —F A60 a, b, c, d,e, f or g —Cl —OCH₃ —CH₃ A61 a, b, c, d, e, f or g —Cl —OCH₃ —OCH₃ A62a, b, c, d, e, f or g —Cl —OCH₃ —OCH₂CH₃ A63 a, b, c, d, e, f or g —Cl—OCH₃ —CF₃ A64 a, b, c, d, e, f or g —Cl —OCH₃ —OCF₃ A65 a, b, c, d, e,f or g —Cl —OCH₃ —CH₂OCH₃ A66 a, b, c, d, e, f or g —Cl —OCH₃—C(O)OCH₂CH₃ A67 a, b, c, d, e, f or g —Cl —OCH₂CH₃ —H A68 a, b, c, d,e, f or g —Cl —OCH₂CH₃ —Cl A69 a, b, c, d, e, f or g —Cl —OCH₂CH₃ —BrA70 a, b, c, d, e, f or g —Cl —OCH₂CH₃ —F A71 a, b, c, d, e, f or g —Cl—OCH₂CH₃ —CH₃ A72 a, b, c, d, e, f or g —Cl —OCH₂CH₃ —OCH₃ A73 a, b, c,d, e, f or g —Cl —OCH₂CH₃ —OCH₂CH₃ A74 a, b, c, d, e, f or g —Cl—OCH₂CH₃ —CF₃ A75 a, b, c, d, e, f or g —Cl —OCH₂CH₃ —OCF₃ A76 a, b, c,d, e, f or g —Cl —OCH₂CH₃ —CH₂OCH₃ A77 a, b, c, d, e, f or g —Cl—OCH₂CH₃ —C(O)OCH₂CH₃ A78 a, b, c, d, e, f or g —Cl —CF₃ —H A79a, b, c,d, e, f or g —Cl —CF₃ —Cl A80 a, b, c, d, e, f or g —Cl —CF₃ —Br A81 a,b, c, d, e, f or g —Cl —CF₃ —F A82 a, b, c, d, e, f or g —Cl —CF₃ —CH₃A83 a, b, c, d, e, f or g —Cl —CF₃ —OCH₃ A84 a, b, c, d, e, f or g —Cl—CF₃ —OCH₂CH₃ A85 a, b, c, d, e, f or g —Cl —CF₃ —CF₃ A86 a, b, c, d, e,f or g —Cl —CF₃ —OCF₃ A87 a, b, c, d, e, f or g —Cl —CF₃ —CH₂OCH₃ A88 a,b, c, d, e, f or g —Cl —CF₃ —C(O)OCH₂CH₃ A89 a, b, c, d, e, f or g —Cl—OCF₃ —H A90 a, b, c, d, e, f or g —Cl —OCF₃ —Cl A91 a, b, c, d, e, f org —Cl —OCF₃ —Br A92 a, b, c, d, e, f or g —Cl —OCF₃ —F A93 a, b, c, d,e, f or g —Cl —OCF₃ —CH₃ A94 a, b, c, d, e, f or g —Cl —OCF₃ —OCH₃ A95a, b, c, d, e, f or g —Cl —OCF₃ —OCH₂CH₃ A96 a, b, c, d, e, f or g —Cl—OCF₃ —CF₃ A97 a, b, c, d, e, f or g —Cl —OCF₃ —OCF₃ A98 a, b, c, d, e,f or g —Cl —OCF₃ —CH₂OCH₃ A99 a, b, c, d, e, f or g —Cl —OCF₃—C(O)OCH₂CH₃ A100 a, b, c, d, e, f or g —Cl —CH₂OCH₃ —H A101 a, b, c, d,e, f or g —Cl —CH₂OCH₃ —Cl A102 a, b, c, d, e, f or g —Cl —CH₂OCH₃ —BrA103 a, b, c, d, e, f or g —Cl —CH₂OCH₃ —F A104 a, b, c, d, e, f or g—Cl —CH₂OCH₃ —CH₃ A105a, b, c, d, e, f or g —Cl —CH₂OCH₃ —OCH₃ A106 a,b, c, d, e, f or g —Cl —CH₂OCH₃ —OCH₂CH₃ A107 a, b, c, d, e, f or g —Cl—CH₂OCH₃ —CF₃ A108 a, b, c, d, e, f or g —Cl —CH₂OCH₃ —OCF₃ A109 a, b,c, d, e, f or g —Cl —CH₂OCH₃ —CH₂OCH₃ A110 a, b, c, d, e, f or g —Cl—CH₂OCH₃ —C(O)OCH₂CH₃ A111 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃ —HA112 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃ —Cl A113 a, b, c, d, e, f org —Cl —C(O)OCH₂CH₃ —Br A114 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃ —FA115 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃ —CH₃ A116 a, b, c, d, e, for g —Cl —C(O)OCH₂CH₃ —OCH₃ A117 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃—OCH₂CH₃ A118 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃ —CF₃ A119 a, b, c,d, e, f or g —Cl —C(O)OCH₂CH₃ —OCF₃ A120 a, b, c, d, e, f or g —Cl—C(O)OCH₂CH₃ —CH₂OCH₃ A121 a, b, c, d, e, f or g —Cl —C(O)OCH₂CH₃—C(O)OCH₂CH₃ A122 a, b, c, d, e, f or g —F —H —H A123 b, d, e, f or g —F—H —Cl A124 b, d, e, f or g —F —H —Br A125 b, d, e, f or g —F —H —F A126a, b, c, d, e, f or g —F —H —CH₃ A127 a, b, c, d, e, f or g —F —H —OCH₃A128 a, b, c, d, e, f or g —F —H —OCH₂CH₃ A129 a, b, c, d, e, f or g —F—H —CF₃ A130 a, b, c, d, e, f or g —F —H —OCF₃ A131a, b, c, d, e, f or g—F —H —CH₂OCH₃ A132 a, b, c, d, e, f or g —F —H —C(O)OCH₂CH₃ A133 a, b,c, d, e, f or g —F —Cl —H A134 a, b, c, d, e, f or g —F —Cl —Cl A135 a,b, c, d, e, f or g —F —Cl —Br A136 a, b, c, d, e, f or g —F —Cl —F A137a, b, c, d, e, f or g —F —Cl —CH₃ A138 a, b, c, d, e, f or g —F —Cl—OCH₃ A139 a, b, c, d, e, f or g —F —Cl —OCH₂CH₃ A140 a, b, c, d, e, for g —F —Cl —CF₃ A141 a, b, c, d, e, f or g —F —Cl —OCF₃ A142 a, b, c,d, e, f or g —F —Cl —CH₂OCH₃ A143 a, b, c, d, e, f or g —F —Cl—C(O)OCH₂CH₃ A144 a, b, c, d, e, f or g —F —Br —H A145 a, b, c, d, e, for g —F —Br —Cl A146 a, b, c, d, e, f or g —F —Br —Br A147 a, b, c, d,e, f or g —F —Br —F A148 a, b, c, d, e, f or g —F —Br —CH₃ A149 a, b, c,d, e, f or g —F —Br —OCH₃ A150 a, b, c, d, e, f or g —F —Br —OCH₂CH₃A151 a, b, c, d, e, f or g —F —Br —CF₃ A152 a, b, c, d, e, f or g —F —Br—OCF₃ A153 a, b, c, d, e, f or g —F —Br —CH₂OCH₃ A154 a, b, c, d, e, for g —F —Br —C(O)OCH₂CH₃ A155 a, b, c, d, e, f or g —F —F —H A156 a, b,c, d, e, f or g —F —F —Cl A157a, b, c, d, e, f or g —F —F —Br A158 a, c,d, e, f or g —F —F —F A159 a, b, c, d, e, f or g —F —F —CH₃ A160 a, b,c, d, e, f or g —F —F —OCH₃ A161 a, b, c, d, e, f or g —F —F —OCH₂CH₃A162 a, b, c, d, e, f or g —F —F —CF₃ A163 a, b, c, d, e, f or g —F —F—OCF₃ A164 a, b, c, d, e, f or g —F —F —CH₂OCH₃ A165 a, b, c, d, e, f org —F —F —C(O)OCH₂CH₃ A166 a, b, c, d, e, f or g —F —CH₃ —H A167 a, b, c,d, e, f or g —F —CH₃ —Cl A168 a, b, c, d, e, f or g —F —CH₃ —Br A169 a,b, c, d, e, f or g —F —CH₃ —F A170 a, b, c, d, e, f or g —F —CH₃ —CH₃A171 a, b, c, d, e, f or g —F —CH₃ —OCH₃ A172 a, b, c, d, e, f or g —F—CH₃ —OCH₂CH₃ A173 a, b, c, d, e, f or g —F —CH₃ —CF₃ A174 a, b, c, d,e, f or g —F —CH₃ —OCF₃ A175 a, b, c, d, e, f or g —F —CH₃ —CH₂OCH₃ A176a, b, c, d, e, f or g —F —CH₃ —C(O)OCH₂CH₃ A177 a, b, c, d, e, f or g —F—OCH₃ —H A178 a, b, c, d, e, f or g —F —OCH₃ —Cl A179 a, b, c, d, e, for g —F —OCH₃ —Br A180 a, b, c, d, e, f or g —F —OCH₃ —F A181 a, b, c,d, e, f or g —F —OCH₃ —CH₃ A182 a, b, c, d, e, f or g —F —OCH₃ —OCH₃A183a, b, c, d, e, f or g —F —OCH₃ —OCH₂CH₃ A184 a, b, c, d, e, f or g—F —OCH₃ —CF₃ A185 a, b, c, d, e, f or g —F —OCH₃ —OCF₃ A186 a, b, c, d,e, f or g —F —OCH₃ —CH₂OCH₃ A187 a, b, c, d, e, f or g —F —OCH₃—C(O)OCH₂CH₃ A188 a, b, c, d, e, f or g —F —OCH₂CH₃ —H A189 a, b, c, d,e, f or g —F —OCH₂CH₃ —Cl A190 a, b, c, d, e, f or g —F —OCH₂CH₃ —BrA191 a, b, c, d, e, f or g —F —OCH₂CH₃ —F A192 a, b, c, d, e, f or g —F—OCH₂CH₃ —CH₃ A193 a, b, c, d, e, f or g —F —OCH₂CH₃ —OCH₃ A194 a, b, c,d, e, f or g —F —OCH₂CH₃ —OCH₂CH₃ A195 a, b, c, d, e, f or g —F —OCH₂CH₃—CF₃ A196 a, b, c, d, e, f or g —F —OCH₂CH₃ —OCF₃ A197 a, b, c, d, e, for g —F —OCH₂CH₃ —CH₂OCH₃ A198 a, b, c, d, e, f or g —F —OCH₂CH₃—C(O)OCH₂CH₃ A199 a, b, c, d, e, f or g —F —CF₃ —H A200 a, b, c, d, e, for g —F —CF₃ —Cl A201 a, b, c, d, e, f or g —F —CF₃ —Br A202 a, b, c, d,e, f or g —F —CF₃ —F A203 a, b, c, d, e, f or g —F —CF₃ —CH₃ A204 a, b,c, d, e, f or g —F —CF₃ —OCH₃ A205 a, b, c, d, e, f or g —F —CF₃—OCH₂CH₃ A206 a, b, c, d, e, f or g —F —CF₃ —CF₃ A207 a, b, c, d, e, for g —F —CF₃ —OCF₃ A208 a, b, c, d, e, f or g —F —CF₃ —CH₂OCH₃ A209a, b,c, d, e, f or g —F —CF₃ —C(O)OCH₂CH₃ A210 a, b, c, d, e, f or g —F —OCF₃—H A211 a, b, c, d, e, f or g —F —OCF₃ —Cl A212 a, b, c, d, e, f or g —F—OCF₃ —Br A213 a, b, c, d, e, f or g —F —OCF₃ —F A214 a, b, c, d, e, for g —F —OCF₃ —CH₃ A215 a, b, c, d, e, f or g —F —OCF₃ —OCH₃ A216 a, b,c, d, e, f or g —F —OCF₃ —OCH₂CH₃ A217 a, b, c, d, e, f or g —F —OCF₃—CF₃ A218 a, b, c, d, e, f or g —F —OCF₃ —OCF₃ A219 a, b, c, d, e, f org —F —OCF₃ —CH₂OCH₃ A220 a, b, c, d, e, f or g —F —OCF₃ —C(O)OCH₂CH₃A221 a, b, c, d, e, f or g —F —CH₂OCH₃ —H A222 a, b, c, d, e, f or g —F—CH₂OCH₃ —Cl A223 a, b, c, d, e, f or g —F —CH₂OCH₃ —Br A224 a, b, c, d,e, f or g —F —CH₂OCH₃ —F A225 a, b, c, d, e, f or g —F —CH₂OCH₃ —CH₃A226 a, b, c, d, e, f or g —F —CH₂OCH₃ —OCH₃ A227 a, b, c, d, e, f or g—F —CH₂OCH₃ —OCH₂CH₃ A228 a, b, c, d, e, f or g —F —CH₂OCH₃ —CF₃ A229 a,b, c, d, e, f or g —F —CH₂OCH₃ —OCF₃ A230 a, b, c, d, e, f or g —F—CH₂OCH₃ —CH₂OCH₃ A231 a, b, c, d, e, f or g —F —CH₂OCH₃ —C(O)OCH₂CH₃A232 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —H A233 a, b, c, d, e, f or g—F —C(O)OCH₂CH₃ —Cl A234 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —BrA235a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —F A236 a, b, c, d, e, f or g—F —C(O)OCH₂CH₃ —CH₃ A237 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —OCH₃A238 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —OCH₂CH₃ A239 a, b, c, d, e,f or g —F —C(O)OCH₂CH₃ —CF₃ A240 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃—OCF₃ A241 a, b, c, d, e, f or g —F —C(O)OCH₂CH₃ —CH₂OCH₃ A242 a, b, c,d, e, f or g —F —C(O)OCH₂CH₃ —C(O)OCH₂CH₃ A243 a, b, c, d, e, f or g—CF₃ —H —H A244 b, d, e, f or g —CF₃ —H —Cl A245 b, d, e, f or g —CF₃ —H—Br A246 b, d, e, f or g —CF₃ —H —F A247 a, b, c, d, e, f or g —CF₃ —H—CH₃ A248 a, b, c, d, e, f or g —CF₃ —H —OCH₃ A249 a, b, c, d, e, f or g—CF₃ —H —OCH₂CH₃ A250 a, b, c, d, e, f or g —CF₃ —H —CF₃ A251 a, b, c,d, e, f or g —CF₃ —H —OCF₃ A252 a, b, c, d, e, f or g —CF₃ —H —CH₂OCH₃A253 a, b, c, d, e, f or g —CF₃ —H —C(O)OCH₂CH₃ A254 a, b, c, d, e, f org —CF₃ —Cl —H A255 a, b, c, d, e, f or g —CF₃ —Cl —Cl A256 a, b, c, d,e, f or g —CF₃ —Cl —Br A257 a, b, c, d, e, f or g —CF₃ —Cl —F A258 a, b,c, d, e, f or g —CF₃ —Cl —CH₃ A259 a, b, c, d, e, f or g —CF₃ —Cl —OCH₃A260 a, b, c, d, e, f or g —CF₃ —Cl —OCH₂CH₃ A261a, b, c, d, e, f or g—CF₃ —Cl —CF₃ A262 a, b, c, d, e, f or g —CF₃ —Cl —OCF₃ A263 a, b, c, d,e, f or g —CF₃ —Cl —CH₂OCH₃ A264 a, b, c, d, e, f or g —CF₃ —Cl—C(O)OCH₂CH₃ A265 a, b, c, d, e, f or g —CF₃ —Br —H A266 a, b, c, d, e,f or g —CF₃ —Br —Cl A267 a, b, c, d, e, f or g —CF₃ —Br —Br A268 a, b,c, d, e, f or g —CF₃ —Br —F A269 a, b, c, d, e, f or g —CF₃ —Br —CH₃A270 a, b, c, d, e, f or g —CF₃ —Br —OCH₃ A271 a, b, c, d, e, f or g—CF₃ —Br —OCH₂CH₃ A272 a, b, c, d, e, f or g —CF₃ —Br —CF₃ A273 a, b, c,d, e, f or g —CF₃ —Br —OCF₃ A274 a, b, c, d, e, f or g —CF₃ —Br —CH₂OCH₃A275 a, b, c, d, e, f or g —CF₃ —Br —C(O)OCH₂CH₃ A276 a, b, c, d, e, for g —CF₃ —F —H A277 a, b, c, d, e, f or g —CF₃ —F —Cl A278 a, b, c, d,e, f or g —CF₃ —F —Br A279 a, c, d, e, f or g —CF₃ —F —F A280 a, b, c,d, e, f or g —CF₃ —F —CH₃ A281 a, b, c, d, e, f or g —CF₃ —F —OCH₃ A282a, b, c, d, e, f or g —CF₃ —F —OCH₂CH₃ A283 a, b, c, d, e, f or g —CF₃—F —CF₃ A284 a, b, c, d, e, f or g —CF₃ —F —OCF₃ A285 a, b, c, d, e, for g —CF₃ —F —CH₂OCH₃ A286 a, b, c, d, e, f or g —CF₃ —F —C(O)OCH₂CH₃A287a, b, c, d, e, f or g —CF₃ —CH₃ —H A288 a, b, c, d, e, f or g —CF₃—CH₃ —Cl A289 a, b, c, d, e, f or g —CF₃ —CH₃ —Br A290 a, b, c, d, e, for g —CF₃ —CH₃ —F A291 a, b, c, d, e, f or g —CF₃ —CH₃ —CH₃ A292 a, b,c, d, e, f or g —CF₃ —CH₃ —OCH₃ A293 a, b, c, d, e, f or g —CF₃ —CH₃—OCH₂CH₃ A294 a, b, c, d, e, f or g —CF₃ —CH₃ —CF₃ A295 a, b, c, d, e, for g —CF₃ —CH₃ —OCF₃ A296 a, b, c, d, e, f or g —CF₃ —CH₃ —CH₂OCH₃ A297a, b, c, d, e, f or g —CF₃ —CH₃ —C(O)OCH₂CH₃ A298 a, b, c, d, e, f or g—CF₃ —OCH₃ —H A299 a, b, c, d, e, f or g —CF₃ —OCH₃ —Cl A300 a, b, c, d,e, f or g —CF₃ —OCH₃ —Br A301 a, b, c, d, e, f or g —CF₃ —OCH₃ —F A302a, b, c, d, e, f or g —CF₃ —OCH₃ —CH₃ A303 a, b, c, d, e, f or g —CF₃—OCH₃ —OCH₃ A304 a, b, c, d, e, f or g —CF₃ —OCH₃ —OCH₂CH₃ A305 a, b, c,d, e, f or g —CF₃ —OCH₃ —CF₃ A306 a, b, c, d, e, f or g —CF₃ —OCH₃ —OCF₃A307 a, b, c, d, e, f or g —CF₃ —OCH₃ —CH₂OCH₃ A308 a, b, c, d, e, f org —CF₃ —OCH₃ —C(O)OCH₂CH₃ A309 a, b, c, d, e, f or g —CF₃ —OCH₂CH₃ —HA310 a, b, c, d, e, f or g —CF₃ —OCH₂CH₃ —Cl A311 a, b, c, d, e, f or g—CF₃ —OCH₂CH₃ —Br A312 a, b, c, d, e, f or g —CF₃ —OCH₂CH₃ —F A313a, b,c, d, e, f or g —CF₃ —OCH₂CH₃ —CH₃ A314 a, b, c, d, e, f or g —CF₃—OCH₂CH₃ —OCH₃ A315 a, b, c, d, e, f or g —CF₃ —OCH₂CH₃ —OCH₂CH₃ A316 a,b, c, d, e, f or g —CF₃ —OCH₂CH₃ —CF₃ A317 a, b, c, d, e, f or g —CF₃—OCH₂CH₃ —OCF₃ A318 a, b, c, d, e, f or g —CF₃ —OCH₂CH₃ —CH₂OCH₃ A319 a,b, c, d, e, f or g —CF₃ —OCH₂CH₃ —C(O)OCH₂CH₃ A320 a, b, c, d, e, f or g—CF₃ —CF₃ —H A321 a, b, c, d, e, f or g —CF₃ —CF₃ —Cl A322 a, b, c, d,e, f or g —CF₃ —CF₃ —Br A323 a, b, c, d, e, f or g —CF₃ —CF₃ —F A324 a,b, c, d, e, f or g —CF₃ —CF₃ —CH₃ A325 a, b, c, d, e, f or g —CF₃ —CF₃—OCH₃ A326 a, b, c, d, e, f or g —CF₃ —CF₃ —OCH₂CH₃ A327 a, b, c, d, e,f or g —CF₃ —CF₃ —CF₃ A328 a, b, c, d, e, f or g —CF₃ —CF₃ —OCF₃ A329 a,b, c, d, e, f or g —CF₃ —CF₃ —CH₂OCH₃ A330 a, b, c, d, e, f or g —CF₃—CF₃ —C(O)OCH₂CH₃ A331 a, b, c, d, e, f or g —CF₃ —OCF₃ —H A332 a, b, c,d, e, f or g —CF₃ —OCF₃ —Cl A333 a, b, c, d, e, f or g —CF₃ —OCF₃ —BrA334 a, b, c, d, e, f or g —CF₃ —OCF₃ —F A335 a, b, c, d, e, f or g —CF₃—OCF₃ —CH₃ A336 a, b, c, d, e, f or g —CF₃ —OCF₃ —OCH₃ A337 a, b, c, d,e, f or g —CF₃ —OCF₃ —OCH₂CH₃ A338 a, b, c, d, e, f or g —CF₃ —OCF₃ —CF₃A339a, b, c, d, e, f or g —CF₃ —OCF₃ —OCF₃ A340 a, b, c, d, e, f or g—CF₃ —OCF₃ —CH₂OCH₃ A341 a, b, c, d, e, f or g —CF₃ —OCF₃ —C(O)OCH₂CH₃A342 a, b, c, d, e, f or g —CF₃ —CH₂OCH₃ —H A343 a, b, c, d, e, f or g—CF₃ —CH₂OCH₃ —Cl A344 a, b, c, d, e, f or g —CF₃ —CH₂OCH₃ —Br A345 a,b, c, d, e, f or g —CF₃ —CH₂OCH₃ —F A346 a, b, c, d, e, f or g —CF₃—CH₂OCH₃ —CH₃ A347 a, b, c, d, e, f or g —CF₃ —CH₂OCH₃ —OCH₃ A348 a, b,c, d, e, f or g —CF₃ —CH₂OCH₃ —OCH₂CH₃ A349 a, b, c, d, e, f or g —CF₃—CH₂OCH₃ —CF₃ A350 a, b, c, d, e, f or g —CF₃ —CH₂OCH₃ —OCF₃ A351 a, b,c, d, e, f or g —CF₃ —CH₂OCH₃ —CH₂OCH₃ A352 a, b, c, d, e, f or g —CF₃—CH₂OCH₃ —C(O)OCH₂CH₃ A353 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃ —HA354 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃ —Cl A355 a, b, c, d, e, for g —CF₃ —C(O)OCH₂CH₃ —Br A356 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃—F A357 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃ —CH₃ A358 a, b, c, d, e,f or g —CF₃ —C(O)OCH₂CH₃ —OCH₃ A359 a, b, c, d, e, f or g —CF₃—C(O)OCH₂CH₃ —OCH₂CH₃ A360 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃ —CF₃A361 a, b, c, d, e, f or g —CF₃ —C(O)OCH₂CH₃ —OCF₃ A362 a, b, c, d, e, for g —CF₃ —C(O)OCH₂CH₃ —CH₂OCH₃ A363 a, b, c, d, e, f or g —CF₃—C(O)OCH₂CH₃ —C(O)OCH₂CH₃

TABLE 2 (h)

(i)

(j)

(k)

(m)

(n)

(o)

(p)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₈ R₉ B B1h, i, j, k, m, n, o or p —Cl —H —H B2 j, k, o or p —Cl —H —ClB3 j, k, o or p —Cl —H —Br B4 j, k, o or p —Cl —H —F B5 h, i, j, k, m,n, o or p —Cl —H —CH₃ B6 h, i, j, k, m, n, o or p —Cl —H —OCH₃ B7 h, i,j, k, m, n, o or p —Cl —H —OCH₂CH₃ B8 h, i, j, k, m, n, o or p —Cl —H—CF₃ B9 h, i, j, k, m, n, o or p —Cl —H —OCF₃ B10 h, i, j, k, m, n, o orp —Cl —H —CH₂OCH₃ B11 h, i, j, k, m, n, o or p —Cl —H —C(O)OCH₂CH₃ B12h, i, j, k, m, n, o or p —Cl —Cl —H B13 h, i, j, k, m, n, o or p —Cl —Cl—Cl B14 h, i, j, k, m, n, o or p —Cl —Cl —Br B15 h, i, j, k, m, n, o orp —Cl —Cl —F B16 h, i, j, k, m, n, o or p —Cl —Cl —CH₃ B17 h, i, j, k,m, n, o or p —Cl —Cl —OCH₃ B18 h, i, j, k, m, n, o or p —Cl —Cl —OCH₂CH₃B19 h, i, j, k, m, n, o or p —Cl —Cl —CF₃ B20 h, i, j, k, m, n, o or p—Cl —Cl —OCF₃ B21 h, i, j, k, m, n, o or p —Cl —Cl —CH₂OCH₃ B22 h, i, j,k, m, n, o or p —Cl —Cl —C(O)OCH₂CH₃ B23 h, i, j, k, m, n, o or p —Cl—Br —H B24 h, i, j, k, m, n, o or p —Cl —Br —Cl B25 h, i, j, k, m, n, oor p —Cl —Br —Br B26 h, i, j, k, m, n, o or p —Cl —Br —F B27h, i, j, k,m, n, o or p —Cl —Br —CH₃ B28 h, i, j, k, m, n, o or p —Cl —Br —OCH₃ B29h, i, j, k, m, n, o or p —Cl —Br —OCH₂CH₃ B30 h, i, j, k, m, n, o or p—Cl —Br —CF₃ B31 h, i, j, k, m, n, o or p —Cl —Br —OCF₃ B32 h, i, j, k,m, n, o or p —Cl —Br —CH₂OCH₃ B33 h, i, j, k, m, n, o or p —Cl —Br—C(O)OCH₂CH₃ B34 h, i, j, k, m, n, o or p —Cl —F —H B35 h, i, j, k, m,n, o or p —Cl —F —Cl B36 h, i, j, k, m, n, o or p —Cl —F —Br B37 h, i,j, k, m, n, o or p —Cl —F —F B38 h, i, j, k, m, n, o or p —Cl —F —CH₃B39 h, i, j, k, m, n, o or p —Cl —F —OCH₃ B40 h, i, j, k, m, n, o or p—Cl —F —OCH₂CH₃ B41 h, i, j, k, m, n, o or p —Cl —F —CF₃ B42 h, i, j, k,m, n, o or p —Cl —F —OCF₃ B43 h, i, j, k, m, n, o or p —Cl —F —CH₂OCH₃B44 h, i, j, k, m, n, o or p —Cl —F —C(O)OCH₂CH₃ B45 h, i, j, k, m, n, oor p —Cl —CH₃ —H B46 h, i, j, k, m, n, o or p —Cl —CH₃ —Cl B47 h, i, j,k, m, n, o or p —Cl —CH₃ —Br B48 h, i, j, k, m, n, o or p —Cl —CH₃ —FB49 h, i, j, k, m, n, o or p —Cl —CH₃ —CH₃ B50 h, i, j, k, m, n, o or p—Cl —CH₃ —OCH₃ B51 h, i, j, k, m, n, o or p —Cl —CH₃ —OCH₂CH₃ B52 h, i,j, k, m, n, o or p —Cl —CH₃ —CF₃ B53h, i, j, k, m, n, o or p —Cl —CH₃—OCF₃ B54 h, i, j, k, m, n, o or p —Cl —CH₃ —CH₂OCH₃ B55 h, i, j, k, m,n, o or p —Cl —CH₃ —C(O)OCH₂CH₃ B56 h, i, j, k, m, n, o or p —Cl —OCH₃—H B57 h, i, j, k, m, n, o or p —Cl —OCH₃ —Cl B58 h, i, j, k, m, n, o orp —Cl —OCH₃ —Br B59 h, i, j, k, m, n, o or p —Cl —OCH₃ —F B60 h, i, j,k, m, n, o or p —Cl —OCH₃ —CH₃ B61 h, i, j, k, m, n, o or p —Cl —OCH₃—OCH₃ B62 h, i, j, k, m, n, o or p —Cl —OCH₃ —OCH₂CH₃ B63 h, i, j, k, m,n, o or p —Cl —OCH₃ —CF₃ B64 h, i, j, k, m, n, o or p —Cl —OCH₃ —OCF₃B65 h, i, j, k, m, n, o or p —Cl —OCH₃ —CH₂OCH₃ B66 h, i, j, k, m, n, oor p —Cl —OCH₃ —C(O)OCH₂CH₃ B67 h, i, j, k, m, n, o or p —Cl —OCH₂CH₃ —HB68 h, i, j, k, m, n, o or p —Cl —OCH₂CH₃ —Cl B69 h, i, j, k, m, n, o orp —Cl —OCH₂CH₃ —Br B70 h, i, j, k, m, n, o or p —Cl —OCH₂CH₃ —F B71 h,i, j, k, m, n, o or p —Cl —OCH₂CH₃ —CH₃ B72 h, i, j, k, m, n, o or p —Cl—OCH₂CH₃ —OCH₃ B73 h, i, j, k, m, n, o or p —Cl —OCH₂CH₃ —OCH₂CH₃ B74 h,i, j, k, m, n, o or p —Cl —OCH₂CH₃ —CF₃ B75 h, i, j, k, m, n, o or p —Cl—OCH₂CH₃ —OCF₃ B76 h, i, j, k, m, n, o or p —Cl —OCH₂CH₃ —CH₂OCH₃ B77 h,i, j, k, m, n, o or p —Cl —OCH₂CH₃ —C(O)OCH₂CH₃ B78 h, i, j, k, m, n, oor p —Cl —CF₃ —H B79h, i, j, k, m, n, o or p —Cl —CF₃ —Cl B80 h, i, j,k, m, n, o or p —Cl —CF₃ —Br B81 h, i, j, k, m, n, o or p —Cl —CF₃ —FB82 h, i, j, k, m; n, o or p —Cl —CF₃ —CH₃ B83 h, i, j, k, m, n, o or p—Cl —CF₃ —OCH₃ B84 h, i, j, k, m, n, o or p —Cl —CF₃ —OCH₂CH₃ B85 h, i,j, k, m, n, o or p —Cl —CF₃ —CF₃ B86 h, i, j, k, m, n, o or p —Cl —CF₃—OCF₃ B87 h, i, j, k, m, n, o or p —Cl —CF₃ —CH₂OCH₃ B88 h, i, j, k, m,n, o or p —Cl —CF₃ —C(O)OCH₂CH₃ B89 h, i, j, k, m, n, o or p —Cl —OCF₃—H B90 h, i, j, k, m, n, o or p —Cl —OCF₃ —Cl B91 h, i, j, k, m, n, o orp —Cl —OCF₃ —Br B92 h, i, j, k, m, n, o or p —Cl —OCF₃ —F B93 h, i, j,k, m, n, o or p —Cl —OCF₃ —CH₃ B94 h, i, j, k, m, n, o or p —Cl —OCF₃—OCH₃ B95 h, i, j, k, m, n, o or p —Cl —OCF₃ —OCH₂CH₃ B96 h, i, j, k, m,n, o or p —Cl —OCF₃ —CF₃ B97 h, i, j, k, m, n, o or p —Cl —OCF₃ —OCF₃B98 h, i, j, k, m, n, o or p —Cl —OCF₃ —CH₂OCH₃ B99 h, i, j, k, m, n, oor p —Cl —OCF₃ —C(O)OCH₂CH₃ B100 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃—H B101 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃ —Cl B102 h, i, j, k, m, n,o or p —Cl —CH₂OCH₃ —Br B103 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃ —FB104 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃ —CH₃ B105h, i, j, k, m, n, oor p —Cl —CH₂OCH₃ —OCH₃ B106 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃—OCH₂CH₃ B107 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃ —CF₃ B108 h, i, j,k, m, n, o or p —Cl —CH₂OCH₃ —OCF₃ B109 h, i, j, k, m, n, o or p —Cl—CH₂OCH₃ —CH₂OCH₃ B110 h, i, j, k, m, n, o or p —Cl —CH₂OCH₃—C(O)OCH₂CH₃ B111 h, i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃ —H B112 h,i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃ —Cl B113 h, i, j, k, m, n, o or p—Cl —C(O)OCH₂CH₃ —Br B114 h, i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃ —FB115 h, i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃ —CH₃ B116 h, i, j, k, m,n, o or p —Cl —C(O)OCH₂CH₃ —OCH₃ B117 h, i, j, k, m, n, o or p —Cl—C(O)OCH₂CH₃ —OCH₂CH₃ B118 h, i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃—CF₃ B119 h, i, j, k, m, n, o or p —Cl —C(O)OCH₂CH₃ —OCF₃ B120 h, i, j,k, m, n, o or p —Cl —C(O)OCH₂CH₃ —CH₂OCH₃ B121 h, i, j, k, m, n, o or p—Cl —C(O)OCH₂CH₃ —C(O)OCH₂CH₃ B122 h, i, j, k, m, n, o or p —F —H —HB123 j, k, o or p —F —H —Cl B124 j, k, o or p —F —H —Br B125 j, k, o orp —F —H —F B126 h, i, j, k, m, n, o or p —F —H —CH₃ B127 h, i, j, k, m,n, o or p —F —H —OCH₃ B128 h, i, j, k, m, n, o or p —F —H —OCH₂CH₃ B129h, i, j, k, m, n, o or p —F —H —CF₃ B130 h, i, j, k, m, n, o or p —F —H—OCF₃ B131h, i, j, k, m, n, o or p —F —H —CH₂OCH₃ B132 h, i, j, k, m, n,o or p —F —H —C(O)OCH₂CH₃ B133 h, i, j, k, m, n, o or p —F —Cl —H B134h, i, j, k, m, n, o or p —F —Cl —Cl B135 h, i, j, k, m, n, o or p —F —Cl—Br B136 h, i, j, k, m, n, o or p —F —Cl —F B137 h, i, j, k, m, n, o orp —F —Cl —CH₃ B138 h, i, j, k, m, n, o or p —F —Cl —OCH₃ B139 h, i, j,k, m, n, o or p —F —Cl —OCH₂CH₃ B140 h, i, j, k, m, n, o or p —F —Cl—CF₃ B141 h, i, j, k, m, n, o or p —F —Cl —OCF₃ B142 h, i, j, k, m, n, oor p —F —Cl —CH₂OCH₃ B143 h, i, j, k, m, n, o or p —F —Cl —C(O)OCH₂CH₃B144 h, i, j, k, m, n, o or p —F —Br —H B145 h, i, j, k, m, n, o or p —F—Br —Cl B146 h, i, j, k, m, n, o or p —F —Br —Br B147 h, i, j, k, m, n,o or p —F —Br —F B148 h, i, j, k, m, n, o or p —F —Br —CH₃ B149 h, i, j,k, m, n, o or p —F —Br —OCH₃ B150 h, i, j, k, m, n, o or p —F —Br—OCH₂CH₃ B151 h, i, j, k, m, n, o or p —F —Br —CF₃ B152 h, i, j, k, m,n, o or p —F —Br —OCF₃ B153 h, i, j, k, m, n, o or p —F —Br —CH₂OCH₃B154 h, i, j, k, m, n, o or p —F —Br —C(O)OCH₂CH₃ B155 h, i, j, k, m, n,o or p —F —F —H B156 h, i, j, k, m, n, o or p —F —F —Cl B157h, i, j, k,m, n, o or p —F —F —Br B158 h, i, j, k, m, n, o or p —F —F —F B159 h, i,j, k, m, n, o or p —F —F —CH₃ B160 h, i, j, k, m, n, o or p —F —F —OCH₃B161 h, i, j, k, m, n, o or p —F —F —OCH₂CH₃ B162 h, i, j, k, m, n, o orp —F —F —CF₃ B163 h, i, j, k, m, n, o or p —F —F —OCF₃ B164 h, i, j, k,m, n, o or p —F —F —CH₂OCH₃ B165 h, i, j, k, m, n, o or p —F —F—C(O)OCH₂CH₃ B166 h, i, j, k, m, n, o or p —F —CH₃ —H B167 h, i, j, k,m, n, o or p —F —CH₃ —Cl B168 h, i, j, k, m, n, o or p —F —CH₃ —Br B169h, i, j, k, m, n, o or p —F —CH₃ —F B170 h, i, j, k, m, n, o or p —F—CH₃ —CH₃ B171 h, i, j, k, m, n, o or p —F —CH₃ —OCH₃ B172 h, i, j, k,m, n, o or p —F —CH₃ —OCH₂CH₃ B173 h, i, j, k, m, n, o or p —F —CH₃ —CF₃B174 h, i, j, k, m, n, o or p —F —CH₃ —OCF₃ B175 h, i, j, k, m, n, o orp —F —CH₃ —CH₂OCH₃ B176 h, i, j, k, m, n, o or p —F —CH₃ —C(O)OCH₂CH₃B177 h, i, j, k, m, n, o or p —F —OCH₃ —H B178 h, i, j, k, m, n, o or p—F —OCH₃ —Cl B179 h, i, j, k, m, n, o or p —F —OCH₃ —Br B180 h, i, j, k,m, n, o or p —F —OCH₃ —F B181 h, i, j, k, m, n, o or p —F —OCH₃ —CH₃B182 h, i, j, k, m, n, o or p —F —OCH₃ —OCH₃ B183h, i, j, k, m, n, o orp —F —OCH₃ —OCH₂CH₃ B184 h, i, j, k, m, n, o or p —F —OCH₃ —CF₃ B185 h,i, j, k, m, n, o or p —F —OCH₃ —OCF₃ B186 h, i, j, k, m, n, o or p —F—OCH₃ —CH₂OCH₃ B187 h, i, j, k, m, n, o or p —F —OCH₃ —C(O)OCH₂CH₃ B188h, i, j, k, m, n, o or p —F —OCH₂CH₃ —H B189 h, i, j, k, m, n, o or p —F—OCH₂CH₃ —Cl B190 h, i, j, k, m, n, o or p —F —OCH₂CH₃ —Br B191 h, i, j,k, m, n, o or p —F —OCH₂CH₃ —F B192 h, i, j, k, m, n, o or p —F —OCH₂CH₃—CH₃ B193 h, i, j, k, m, n, o or p —F —OCH₂CH₃ —OCH₃ B194 h, i, j, k, m,n, o or p —F —OCH₂CH₃ —OCH₂CH₃ B195 h, i, j, k, m, n, o or p —F —OCH₂CH₃—CF₃ B196 h, i, j, k, m, n, o or p —F —OCH₂CH₃ —OCF₃ B197 h, i, j, k, m,n, o or p —F —OCH₂CH₃ —CH₂OCH₃ B198 h, i, j, k, m, n, o or p —F —OCH₂CH₃—C(O)OCH₂CH₃ B199 h, i, j, k, m, n, o or p —F —CF₃ —H B200 h, i, j, k,m, n, o or p —F —CF₃ —Cl B201 h, i, j, k, m, n, o or p —F —CF₃ —Br B202h, i, j, k, m, n, o or p —F —CF₃ —F B203 h, i, j, k, m, n, o or p —F—CF₃ —CH₃ B204 h, i, j, k, m, n, o or p —F —CF₃ —OCH₃ B205 h, i, j, k,m, n, o or p —F —CF₃ —OCH₂CH₃ B206 h, i, j, k, m, n, o or p —F —CF₃ —CF₃B207 h, i, j, k, m, n, o or p —F —CF₃ —OCF₃ B208 h, i, j, k, m, n, o orp —F —CF₃ —CH₂OCH₃ B209h, i, j, k, m, n, o or p —F —CF₃ —C(O)OCH₂CH₃B210 h, i, j, k, m, n, o or p —F —OCF₃ —H B211 h, i, j, k, m, n, o or p—F —OCF₃ —Cl B212 h, i, j, k, m, n, o or p —F —OCF₃ —Br B213 h, i, j, k,m, n, o or p —F —OCF₃ —F B214 h, i, j, k, m, n, o or p —F —OCF₃ —CH₃B215 h, i, j, k, m, n, o or p —F —OCF₃ —OCH₃ B216 h, i, j, k, m, n, o orp —F —OCF₃ —OCH₂CH₃ B217 h, i, j, k, m, n, o or p —F —OCF₃ —CF₃ B218 h,i, j, k, m, n, o or p —F —OCF₃ —OCF₃ B219 h, i, j, k, m, n, o or p —F—OCF₃ —CH₂OCH₃ B220 h, i, j, k, m, n, o or p —F —OCF₃ —C(O)OCH₂CH₃ B221h, i, j, k, m, n, o or p —F —CH₂OCH₃ —H B222 h, i, j, k, m, n, o or p —F—CH₂OCH₃ —Cl B223 h, i, j, k, m, n, o or p —F —CH₂OCH₃ —Br B224 h, i, j,k, m, n, o or p —F —CH₂OCH₃ —F B225 h, i, j, k, m, n, o or p —F —CH₂OCH₃—CH₃ B226 h, i, j, k, m, n, o or p —F —CH₂OCH₃ —OCH₃ B227 h, i, j, k, m,n, o or p —F —CH₂OCH₃ —OCH₂CH₃ B228 h, i, j, k, m, n, o or p —F —CH₂OCH₃—CF₃ B229 h, i, j, k, m, n, o or p —F —CH₂OCH₃ —OCF₃ B230 h, i, j, k, m,n, o or p —F —CH₂OCH₃ —CH₂OCH₃ B231 h, i, j, k, m, n, o or p —F —CH₂OCH₃—C(O)OCH₂CH₃ B232 h, i, j, k, m, n, o or p —F —C(O)OCH₂CH₃ —H B233 h, i,j, k, m, n, o or p —F —C(O)OCH₂CH₃ —Cl B234 h, i, j, k, m, n, o or p —F—C(O)OCH₂CH₃ —Br B235h, i, j, k, m, n, o or p —F —C(O)OCH₂CH₃ —F B236 h,i, j, k, m, n, o or p —F —C(O)OCH₂CH₃ —CH₃ B237 h, i, j, k, m, n, o or p—F —C(O)OCH₂CH₃ —OCH₃ B238 h, i, j, k, m, n, o or p —F —C(O)OCH₂CH₃—OCH₂CH₃ B239 h, I, j, k, m, n, o or p —F —C(O)OCH₂CH₃ —CF₃ B240 h, i,j, k, m, n, o or p —F —C(O)OCH₂CH₃ —OCF₃ B241 h, i, j, k, m, n, o or p—F —C(O)OCH₂CH₃ —CH₂OCH₃ B242 h, i, j, k, m, n, o or p —F —C(O)OCH₂CH₃—C(O)OCH₂CH₃ B243 h, i, j, k, m, n, o or p —CF₃ —H —H B244 j, k, o or p—CF₃ —H —Cl B245 j, k, o or p —CF₃ —H —Br B246 j, k, o or p —CF₃ —H —FB247 h, i, j, k, m, n, o or p —CF₃ —H —CH₃ B248 h, i, j, k, m, n, o or p—CF₃ —H —OCH₃ B249 h, i, j, k, m, n, o or p —CF₃ —H —OCH₂CH₃ B250 h, i,j, k, m, n, o or p —CF₃ —H —CF₃ B251 h, i, j, k, m, n, o or p —CF₃ —H—OCF₃ B252 h, i, j, k, m, n, o or p —CF₃ —H —CH₂OCH₃ B253 h, i, j, k, m,n, o or p —CF₃ —H —C(O)OCH₂CH₃ B254 h, i, j, k, m, n, o or p —CF₃ —Cl —HB255 h, i, j, k, m, n, o or p —CF₃ —Cl —Cl B256 h, i, j, k, m, n, o or p—CF₃ —Cl —Br B257 h, i, j, k, m, n, o or p —CF₃ —Cl —F B258 h, i, j, k,m, n, o or p —CF₃ —Cl —CH₃ B259 h, i, j, k, m, n, o or p —CF₃ —Cl —OCH₃B260 h, i, j, k, m, n, o or p —CF₃ —Cl —OCH₂CH₃ B261h, i, j, k, m, n, oor p —CF₃ —Cl —CF₃ B262 h, i, j, k, m, n, o or p —CF₃ —Cl —OCF₃ B263 h,i, j, k, m, n, o or p —CF₃ —Cl —CH₂OCH₃ B264 h, i, j, k, m, n, o or p—CF₃ —Cl —C(O)OCH₂CH₃ B265 h, i, j, k, m, n, o or p —CF₃ —Br —H B266 h,i, j, k, m, n, o or p —CF₃ —Br —Cl B267 h, i, j, k, m, n, o or p —CF₃—Br —Br B268 h, i, j, k, m, n, o or p —CF₃ —Br —F B269 h, i, j, k, m, n,o or p —CF₃ —Br —CH₃ B270 h, i, j, k, m, n, o or p —CF₃ —Br —OCH₃ B271h, i, j, k, m, n, o or p —CF₃ —Br —OCH₂CH₃ B272 h, i, j, k, m, n, o or p—CF₃ —Br —CF₃ B273 h, i, j, k, m, n, o or p —CF₃ —Br —OCF₃ B274 h, i, j,k, m, n, o or p —CF₃ —Br —CH₂OCH₃ B275 h, i, j, k, m, n, o or p —CF₃ —Br—C(O)OCH₂CH₃ B276 h, i, j, k, m, n, o or p —CF₃ —F —H B277 h, i, j, k,m, n, o or p —CF₃ —F —Cl B278 h, i, j, k, m, n, o or p —CF₃ —F —Br B279h, i, j, k, m, n, o or p —CF₃ —F —F B280 h, i, j, k, m, n, o or p —CF₃—F —CH₃ B281 h, i, j, k, m, n, o or p —CF₃ —F —OCH₃ B282 h, i, j, k, m,n, o or p —CF₃ —F —OCH₂CH₃ B283 h, i, j, k, m, n, o or p —CF₃ —F —CF₃B284 h, i, j, k, m, n, o or p —CF₃ —F —OCF₃ B285 h, i, j, k, m, n, o orp —CF₃ —F —CH₂OCH₃ B286 h, i, j, k, m, n, o or p —CF₃ —F —C(O)OCH₂CH₃B287h, i, j, k, m, n, o or p —CF₃ —CH₃ —H B288 h, i, j, k, m, n, o or p—CF₃ —CH₃ —Cl B289 h, i, j, k, m, n, o or p —CF₃ —CH₃ —Br B290 h, i, j,k, m, n, o or p —CF₃ —CH₃ —F B291 h, i, j, k, m, n, o or p —CF₃ —CH₃—CH₃ B292 h, i, j, k, m, n, o or p —CF₃ —CH₃ —OCH₃ B293 h, i, j, k, m,n, o or p —CF₃ —CH₃ —OCH₂CH₃ B294 h, i, j, k, m, n, o or p —CF₃ —CH₃—CF₃ B295 h, i, j, k, m, n, o or p —CF₃ —CH₃ —OCF₃ B296 h, i, j, k, m,n, o or p —CF₃ —CH₃ —CH₂OCH₃ B297 h, i, j, k, m, n, o or p —CF₃ —CH₃—C(O)OCH₂CH₃ B298 h, i, j, k, m, n, o or p —CF₃ —OCH₃ —H B299 h, i, j,k, m, n, o or p —CF₃ —OCH₃ —Cl B300 h, i, j, k, m, n, o or p —CF₃ —OCH₃—Br B301 h, i, j, k, m, n, o or p —CF₃ —OCH₃ —F B302 h, i, j, k, m, n, oor p —CF₃ —OCH₃ —CH₃ B303 h, i, j, k, m, n, o or p —CF₃ —OCH₃ —OCH₃ B304h, i, j, k, m, n, o or p —CF₃ —OCH₃ —OCH₂CH₃ B305 h, i, j, k, m, n, o orp —CF₃ —OCH₃ —CF₃ B306 h, i, j, k, m, n, o or p —CF₃ —OCH₃ —OCF₃ B307 h,i, j, k, m, n, o or p —CF₃ —OCH₃ —CH₂OCH₃ B308 h, i, j, k, m, n, o or p—CF₃ —OCH₃ —C(O)OCH₂CH₃ B309 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃ —HB310 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃ —Cl B311 h, i, j, k, m, n, oor p —CF₃ —OCH₂CH₃ —Br B312 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃ —FB313h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃ —CH₃ B314 h, i, j, k, m, n, oor p —CF₃ —OCH₂CH₃ —OCH₃ B315 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃—OCH₂CH₃ B316 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃ —CF₃ B317 h, i, j,k, m, n, o or p —CF₃ —OCH₂CH₃ —OCF₃ B318 h, i, j, k, m, n, o or p —CF₃—OCH₂CH₃ —CH₂OCH₃ B319 h, i, j, k, m, n, o or p —CF₃ —OCH₂CH₃—C(O)OCH₂CH₃ B320 h, i, j, k, m, n, o or p —CF₃ —CF₃ —H B321 h, i, j, k,m, n, o or p —CF₃ —CF₃ —Cl B322 h, i, j, k, m, n, o or p —CF₃ —CF₃ —BrB323 h, i, j, k, m, n, o or p —CF₃ —CF₃ —F B324 h, i, j, k, m, n, o or p—CF₃ —CF₃ —CH₃ B325 h, i, j, k, m, n, o or p —CF₃ —CF₃ —OCH₃ B326 h, i,j, k, m, n, o or p —CF₃ —CF₃ —OCH₂CH₃ B327 h, i, j, k, m, n, o or p —CF₃—CF₃ —CF₃ B328 h, i, j, k, m, n, o or p —CF₃ —CF₃ —OCF₃ B329 h, i, j, k,m, n, o or p —CF₃ —CF₃ —CH₂OCH₃ B330 h, i, j, k, m, n, o or p —CF₃ —CF₃—C(O)OCH₂CH₃ B331 h, i, j, k, m, n, o or p —CF₃ —OCF₃ —H B332 h, i, j,k, m, n, o or p —CF₃ —OCF₃ —Cl B333 h, i, j, k, m, n, o or p —CF₃ —OCF₃—Br B334 h, i, j, k, m, n, o or p —CF₃ —OCF₃ —F B335 h, i, j, k, m, n, oor p —CF₃ —OCF₃ —CH₃ B336 h, i, j, k, m, n, o or p —CF₃ —OCF₃ —OCH₃ B337h, i, j, k, m, n, o or p —CF₃ —OCF₃ —OCH₂CH₃ B338 h, i, j, k, m, n, o orp —CF₃ —OCF₃ —CF₃ B339h, i, j, k, m, n, o or p —CF₃ —OCF₃ —OCF₃ B340 h,i, j, k, m, n, o or p —CF₃ —OCF₃ —CH₂OCH₃ B341 h, i, j, k, m, n, o or p—CF₃ —OCF₃ —C(O)OCH₂CH₃ B342 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃ —HB343 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃ —Cl B344 h, i, j, k, m, n, oor p —CF₃ —CH₂OCH₃ —Br B345 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃ —FB346 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃ —CH₃ B347 h, i, j, k, m, n,o or p —CF₃ —CH₂OCH₃ —OCH₃ B348 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃—OCH₂CH₃ B349 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃ —CF₃ B350 h, i, j,k, m, n, o or p —CF₃ —CH₂OCH₃ —OCF₃ B351 h, i, j, k, m, n, o or p —CF₃—CH₂OCH₃ —CH₂OCH₃ B352 h, i, j, k, m, n, o or p —CF₃ —CH₂OCH₃—C(O)OCH₂CH₃ B353 h, i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃ —H B354 h,i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃ —Cl B355 h, i, j, k, m, n, o orp —CF₃ —C(O)OCH₂CH₃ —Br B356 h, i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃—F B357 h, i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃ —CH₃ B358 h, i, j, k,m, n, o or p —CF₃ —C(O)OCH₂CH₃ —OCH₃ B359 h, i, j, k, m, n, o or p —CF₃—C(O)OCH₂CH₃ —OCH₂CH₃ B360 h, i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃—CF₃ B361 h, i, j, k, m, n, o or p —CF₃ —C(O)OCH₂CH₃ —OCF₃ B362 h, i, j,k, m, n, o or p —CF₃ —C(O)OCH₂CH₃ —CH₂OCH₃ B363 h, i, j, k, m, n, o or p—CF₃ —C(O)OCH₂CH₃ —C(O)OCH₂CH₃

TABLE 3 (q)

(r)

(s)

(t)

and pharmaceutically acceptable derivatives thereof, where: Compound R₁R₈ R₉ C C1q, r, s or t —Cl —H —H C2 q, r, s or t —Cl —H —Cl C3 q, r, sor t —Cl —H —Br C4 q, r, s or t —Cl —H —F C5 q, r, s or t —Cl —H —CH₃ C6q, r, s or t —Cl —H —OCH₃ C7 q, r, s or t —Cl —H —OCH₂CH₃ C8 q, r, s ort —Cl —H —CF₃ C9 q, r, s or t —Cl —H —OCF₃ C10 q, r, s or t —Cl —H—CH₂OCH₃ C11 q, r, s or t —Cl —H —C(O)OCH₂CH₃ C12 q, r, s or t —Cl —Cl—H C13 q, r, s or t —Cl —Cl —Cl C14 q, r, s or t —Cl —Cl —Br C15 q, r, sor t —Cl —Cl —F C16 q, r, s or t —Cl —Cl —CH₃ C17 q, r, s or t —Cl —Cl—OCH₃ C18 q, r, s or t —Cl —Cl —OCH₂CH₃ C19 q, r, s or t —Cl —Cl —CF₃C20 q, r, s or t —Cl —Cl —OCF₃ C21 q, r, s or t —Cl —Cl —CH₂OCH₃ C22 q,r, s or t —Cl —Cl —C(O)OCH₂CH₃ C23 q, r, s or t —Cl —Br —H C24 q, r, sor t —Cl —Br —Cl C25 q, r, s or t —Cl —Br —Br C26 q, r, s or t —Cl —Br—F C27q, r, s or t —Cl —Br —CH₃ C28 q, r, s or t —Cl —Br —OCH₃ C29 q, r,s or t —Cl —Br —OCH₂CH₃ C30 q, r, s or t —Cl —Br —CF₃ C31 q, r, s or t—Cl —Br —OCF₃ C32 q, r, s or t —Cl —Br —CH₂OCH₃ C33 q, r, s or t —Cl —Br—C(O)OCH₂CH₃ C34 q, r, s or t —Cl —F —H C35 q, r, s or t —Cl —F —Cl C36q, r, s or t —Cl —F —Br C37 q, r, s or t —Cl —F —F C38 q, r, s or t —Cl—F —CH₃ C39 q, r, s or t —Cl —F —OCH₃ C40 q, r, s or t —Cl —F —OCH₂CH₃C41 q, r, s or t —Cl —F —CF₃ C42 q, r, s or t —Cl —F —OCF₃ C43 q, r, sor t —Cl —F —CH₂OCH₃ C44 q, r, s or t —Cl —F —C(O)OCH₂CH₃ C45 q, r, s ort —Cl —CH₃ —H C46 q, r, s or t —Cl —CH₃ —Cl C47 q, r, s or t —Cl —CH₃—Br C48 q, r, s or t —Cl —CH₃ —F C49 q, r, s or t —Cl —CH₃ —CH₃ C50 q,r, s or t —Cl —CH₃ —OCH₃ C51 q, r, s or t —Cl —CH₃ —OCH₂CH₃ C52 q, r, sor t —Cl —CH₃ —CF₃ C53q, r, s or t —Cl —CH₃ —OCF₃ C54 q, r, s or t —Cl—CH₃ —CH₂OCH₃ C55 q, r, s or t —Cl —CH₃ —C(O)OCH₂CH₃ C56 q, r, s or t—Cl —OCH₃ —H C57 q, r, s or t —Cl —OCH₃ —Cl C58 q, r, s or t —Cl —OCH₃—Br C59 q, r, s or t —Cl —OCH₃ —F C60 q, r, s or t —Cl —OCH₃ —CH₃ C61 q,r, s or t —Cl —OCH₃ —OCH₃ C62 q, r, s or t —Cl —OCH₃ —OCH₂CH₃ C63 q, r,s or t —Cl —OCH₃ —CF₃ C64 q, r, s or t —Cl —OCH₃ —OCF₃ C65 q, r, s or t—Cl —OCH₃ —CH₂OCH₃ C66 q, r, s or t —Cl —OCH₃ —C(O)OCH₂CH₃ C67 q, r, sor t —Cl —OCH₂CH₃ —H C68 q, r, s or t —Cl —OCH₂CH₃ —Cl C69 q, r, s or t—Cl —OCH₂CH₃ —Br C70 q, r, s or t —Cl —OCH₂CH₃ —F C71 q, r, s or t —Cl—OCH₂CH₃ —CH₃ C72 q, r, s or t —Cl —OCH₂CH₃ —OCH₃ C73 q, r, s or t —Cl—OCH₂CH₃ —OCH₂CH₃ C74 q, r, s or t —Cl —OCH₂CH₃ —CF₃ C75 q, r, s or t—Cl —OCH₂CH₃ —OCF₃ C76 q, r, s or t —Cl —OCH₂CH₃ —CH₂OCH₃ C77 q, r, s ort —Cl —OCH₂CH₃ —C(O)OCH₂CH₃ C78 q, r, s or t —Cl —CF₃ —H C79q, r, s or t—Cl —CF₃ —Cl C80 q, r, s or t —Cl —CF₃ —Br C81 q, r, s or t —Cl —CF₃ —FC82 q, r, s or t —Cl —CF₃ —CH₃ C83 q, r, s or t —Cl —CF₃ —OCH₃ C84 q, r,s or t —Cl —CF₃ —OCH₂CH₃ C85 q, r, s or t —Cl —CF₃ —CF₃ C86 q, r, s or t—Cl —CF₃ —OCF₃ C87 q, r, s or t —Cl —CF₃ —CH₂OCH₃ C88 q, r, s or t —Cl—CF₃ —C(O)OCH₂CH₃ C89 q, r, s or t —Cl —OCF₃ —H C90 q, r, s or t —Cl—OCF₃ —Cl C91 q, r, s or t —Cl —OCF₃ —Br C92 q, r, s or t —Cl —OCF₃ —FC93 q, r, s or t —Cl —OCF₃ —CH₃ C94 q, r, s or t —Cl —OCF₃ —OCH₃ C95 q,r, s or t —Cl —OCF₃ —OCH₂CH₃ C96 q, r, s or t —Cl —OCF₃ —CF₃ C97 q, r, sor t —Cl —OCF₃ —OCF₃ C98 q, r, s or t —Cl —OCF₃ —CH₂OCH₃ C99 q, r, s ort —Cl —OCF₃ —C(O)OCH₂CH₃ C100 q, r, s or t —Cl —CH₂OCH₃ —H C101 q, r, sor t —Cl —CH₂OCH₃ —Cl C102 q, r, s or t —Cl —CH₂OCH₃ —Br C103 q, r, s ort —Cl —CH₂OCH₃ —F C104 q, r, s or t —Cl —CH₂OCH₃ —CH₃ C105q, r, s or t—Cl —CH₂OCH₃ —OCH₃ C106 q, r, s or t —Cl —CH₂OCH₃ —OCH₂CH₃ C107 q, r, sor t —Cl —CH₂OCH₃ —CF₃ C108 q, r, s or t —Cl —CH₂OCH₃ —OCF₃ C109 q, r, sor t —Cl —CH₂OCH₃ —CH₂OCH₃ C110 q, r, s or t —Cl —CH₂OCH₃ —C(O)OCH₂CH₃C111 q, r, s or t —Cl —C(O)OCH₂CH₃ —H C112 q, r, s or t —Cl —C(O)OCH₂CH₃—Cl C113 q, r, s or t —Cl —C(O)OCH₂CH₃ —Br C114 q, r, s or t —Cl—C(O)OCH₂CH₃ —F C115 q, r, s or t —Cl —C(O)OCH₂CH₃ —CH₃ C116 q, r, s ort —Cl —C(O)OCH₂CH₃ —OCH₃ C117 q, r, s or t —Cl —C(O)OCH₂CH₃ —OCH₂CH₃C118 q, r, s or t —Cl —C(O)OCH₂CH₃ —CF₃ C119 q, r, s or t —Cl—C(O)OCH₂CH₃ —OCF₃ C120 q, r, s or t —Cl —C(O)OCH₂CH₃ —CH₂OCH₃ C121 q,r, s or t —Cl —C(O)OCH₂CH₃ —C(O)OCH₂CH₃ C122 q, r, s or t —F —H —H C123q, r, s or t —F —H —Cl C124 q, r, s or t —F —H —Br C125 q, r, s or t —F—H —F C126 q, r, s or t —F —H —CH₃ C127 q, r, s or t —F —H —OCH₃ C128 q,r, s or t —F —H —OCH₂CH₃ C129 q, r, s or t —F —H —CF₃ C130 q, r, s or t—F —H —OCF₃ C131q, r, s or t —F —H —CH₂OCH₃ C132 q, r, s or t —F —H—C(O)OCH₂CH₃ C133 q, r, s or t —F —Cl —H C134 q, r, s or t —F —Cl —ClC135 q, r, s or t —F —Cl —Br C136 q, r, s or t —F —Cl —F C137 q, r, s ort —F —Cl —CH₃ C138 q, r, sor t —F —Cl —OCH₃ C139 q, r, s or t —F —Cl—OCH₂CH₃ C140 q, r, s or t —F —Cl —CF₃ C141 q, r, s or t —F —Cl —OCF₃C142 q, r, s or t —F —Cl —CH₂OCH₃ C143 q, r, s or t —F —Cl —C(O)OCH₂CH₃C144 q, r, s or t —F —Br —H C145 q, r, s or t —F —Br —Cl C146 q, r, s ort —F —Br —Br C147 q, r, s or t —F —Br —F C148 q, r, s or t —F —Br —CH₃C149 q, r, s or t —F —Br —OCH₃ C150 q, r, s or t —F —Br —OCH₂CH₃ C151 q,r, s or t —F —Br —CF₃ C152 q, r, s or t —F —Br —OCF₃ C153 q, r, s or t—F —Br —CH₂OCH₃ C154 q, r, s or t —F —Br —C(O)OCH₂CH₃ C155 q, r, s or t—F —F —H C156 q, r, s or t —F —F —Cl C157q, r, s or t —F —F —Br C158 q,r, s or t —F —F —F C159 q, r, s or t —F —F —CH₃ C160 q, r, s or t —F —F—OCH₃ C161 q, r, s or t —F —F —OCH₂CH₃ C162 q, r, s or t —F —F —CF₃ C163q, r, s or t —F —F —OCF₃ C164 q, r, s or t —F —F —CH₂OCH₃ C165 q, r, sor t —F —F —C(O)OCH₂CH₃ C166 q, r, s or t —F —CH₃ —H C167 q, r, s or t—F —CH₃ —Cl C168 q, r, s or t —F —CH₃ —Br C169 q, r, s or t —F —CH₃ —FC170 q, r, s or t —F —CH₃ —CH₃ C171 q, r, s or t —F —CH₃ —OCH₃ C172 q,r, s or t —F —CH₃ —OCH₂CH₃ C173 q, r, s or t —F —CH₃ —CF₃ C174 q, r, sor t —F —CH₃ —OCF₃ C175 q, r, s or t —F —CH₃ —CH₂OCH₃ C176 q, r, s or t—F —CH₃ —C(O)OCH₂CH₃ C177 q, r, s or t —F —OCH₃ —H C178 q, r, s or t —F—OCH₃ —Cl C179 q, r, s or t —F —OCH₃ —Br C180 q, r, s or t —F —OCH₃ —FC181 q, r, s or t —F —OCH₃ —CH₃ C182 q, r, s or t —F —OCH₃ —OCH₃ C183q,r, s or t —F —OCH₃ —OCH₂CH₃ C184 q, r, s or t —F —OCH₃ —CF₃ C185 q, r, sor t —F —OCH₃ —OCF₃ C186 q, r, s or t —F —OCH₃ —CH₂OCH₃ C187 q, r, s ort —F —OCH₃ —C(O)OCH₂CH₃ C188 q, r, s or t —F —OCH₂CH₃ —H C189 q, r, s ort —F —OCH₂CH₃ —Cl C190 q, r, s or t —F —OCH₂CH₃ —Br C191 q, r, s or t —F—OCH₂CH₃ —F C192 q, r, s or t —F —OCH₂CH₃ —CH₃ C193 q, r, s or t —F—OCH₂CH₃ —OCH₃ C194 q, r, s or t —F —OCH₂CH₃ —OCH₂CH₃ C195 q, r, s or t—F —OCH₂CH₃ —CF₃ C196 q, r, s or t —F —OCH₂CH₃ —OCF₃ C197 q, r, s or t—F —OCH₂CH₃ —CH₂OCH₃ C198 q, r, s or t —F —OCH₂CH₃ —C(O)OCH₂CH₃ C199 q,r, s or t —F —CF₃ —H C200 q, r, s or t —F —CF₃ —Cl C201 q, r, s or t —F—CF₃ —Br C202 q, r, s or t —F —CF₃ —F C203 q, r, s or t —F —CF₃ —CH₃C204 q, r, s or t —F —CF₃ —OCH₃ C205 q, r, s or t —F —CF₃ —OCH₂CH₃ C206q, r, s or t —F —CF₃ —CF₃ C207 q, r, s or t —F —CF₃ —OCF₃ C208 q, r, sor t —F —CF₃ —CH₂OCH₃ C209q, r, s or t —F —CF₃ —C(O)OCH₂CH₃ C210 q, r, sor t —F —OCF₃ —H C211 q, r, s or t —F —OCF₃ —Cl C212 q, r, s or t —F—OCF₃ —Br C213 q, r, s or t —F —OCF₃ —F C214 q, r, s or t —F —OCF₃ —CH₃C215 q, r, s or t —F —OCF₃ —OCH₃ C216 q, r, s or t —F —OCF₃ —OCH₂CH₃C217 q, r, s or t —F —OCF₃ —CF₃ C218 q, r, s or t —F —OCF₃ —OCF₃ C219 q,r, s or t —F —OCF₃ —CH₂OCH₃ C220 q, r, s or t —F —OCF₃ —C(O)OCH₂CH₃ C221q, r, s or t —F —CH₂OCH₃ —H C222 q, r, s or t —F —CH₂OCH₃ —Cl C223 q, r,s or t —F —CH₂OCH₃ —Br C224 q, r, s or t —F —CH₂OCH₃ —F C225 q, r, s ort —F —CH₂OCH₃ —CH₃ C226 q, r, s or t —F —CH₂OCH₃ —OCH₃ C227 q, r, s or t—F —CH₂OCH₃ —OCH₂CH₃ C228 q, r, s or t —F —CH₂OCH₃ —CF₃ C229 q, r, s ort —F —CH₂OCH₃ —OCF₃ C230 q, r, s or t —F —CH₂OCH₃ —CH₂OCH₃ C231 q, r, sor t —F —CH₂OCH₃ —C(O)OCH₂CH₃ C232 q, r, s or t —F —C(O)OCH₂CH₃ —H C233q, r, s or t —F —C(O)OCH₂CH₃ —Cl C234 q, r, s or t —F —C(O)OCH₂CH₃ —BrC235q, r, s or t —F —C(O)OCH₂CH₃ —F C236 q, r, s or t —F —C(O)OCH₂CH₃—CH₃ C237 q, r, s or t —F —C(O)OCH₂CH₃ —OCH₃ C238 q, r, s or t —F—C(O)OCH₂CH₃ —OCH₂CH₃ C239 q, r, s or t —F —C(O)OCH₂CH₃ —CF₃ C240 q, r,s or t —F —C(O)OCH₂CH₃ —OCF₃ C241 q, r, s or t —F —C(O)OCH₂CH₃ —CH₂OCH₃C242 q, r, s or t —F —C(O)OCH₂CH₃ —C(O)OCH₂CH₃ C243 q, r, s or t —CF₃ —H—H C244 q, r, s or t —CF₃ —H —Cl C245 q, r, s or t —CF₃ —H —Br C246 q,r, s or t —CF₃ —H —F C247 q, r, s or t —CF₃ —H —CH₃ C248 q, r, s or t—CF₃ —H —OCH₃ C249 q, r, s or t —CF₃ —H —OCH₂CH₃ C250 q, r, s or t —CF₃—H —CF₃ C251 q, r, s or t —CF₃ —H —OCF₃ C252 q, r, s or t —CF₃ —H—CH₂OCH₃ C253 q, r, s or t —CF₃ —H —C(O)OCH₂CH₃ C254 q, r, s or t —CF₃—Cl —H C255 q, r, s or t —CF₃ —Cl —Cl C256 q, r, s or t —CF₃ —Cl —BrC257 q, r, s or t —CF₃ —Cl —F C258 q, r, s or t —CF₃ —Cl —CH₃ C259 q, r,s or t —CF₃ —Cl —OCH₃ C260 q, r, s or t —CF₃ —Cl —OCH₂CH₃ C261q, r, s ort —CF₃ —Cl —CF₃ C262 q, r, s or t —CF₃ —Cl —OCF₃ C263 q, r, s or t —CF₃—Cl —CH₂OCH₃ C264 q, r, s or t —CF₃ —Cl —C(O)OCH₂CH₃ C265 q, r, s or t—CF₃ —Br —H C266 q, r, s or t —CF₃ —Br —Cl C267 q, r, s or t —CF₃ —Br—Br C268 q, r, s or t —CF₃ —Br —F C269 q, r, s or t —CF₃ —Br —CH₃ C270q, r, s or t —CF₃ —Br —OCH₃ C271 q, r, s or t —CF₃ —Br —OCH₂CH₃ C272 q,r, s or t —CF₃ —Br —CF₃ C273 q, r, s or t —CF₃ —Br —OCF₃ C274 q, r, s ort —CF₃ —Br —CH₂OCH₃ C275 q, r, s or t —CF₃ —Br —C(O)OCH₂CH₃ C276 q, r, sor t —CF₃ —F —H C277 q, r, s or t —CF₃ —F —Cl C278 q, r, s or t —CF₃ —F—Br C279 q, r, s or t —CF₃ —F —F C280 q, r, s or t —CF₃ —F —CH₃ C281 q,r, s or t —CF₃ —F —OCH₃ C282 q, r, s or t —CF₃ —F —OCH₂CH₃ C283 q, r, sor t —CF₃ —F —CF₃ C284 q, r, s or t —CF₃ —F —OCF₃ C285 q, r, s or t —CF₃—F —CH₂OCH₃ C286 q, r, s or t —CF₃ —F —C(O)OCH₂CH₃ C287q, r, s or t —CF₃—CH₃ —H C288 q, r, s or t —CF₃ —CH₃ —Cl C289 q, r, s or t —CF₃ —CH₃ —BrC290 q, r, s or t —CF₃ —CH₃ —F C291 q, r, s or t —CF₃ —CH₃ —CH₃ C292 q,r, s or t —CF₃ —CH₃ —OCH₃ C293 q, r, s or t —CF₃ —CH₃ —OCH₂CH₃ C294 q,r, s or t —CF₃ —CH₃ —CF₃ C295 q, r, s or t —CF₃ —CH₃ —OCF₃ C296 q, r, sor t —CF₃ —CH₃ —CH₂OCH₃ C297 q, r, s or t —CF₃ —CH₃ —C(O)OCH₂CH₃ C298 q,r, s or t —CF₃ —OCH₃ —H C299 q, r, s or t —CF₃ —OCH₃ —Cl C300 q, r, s ort —CF₃ —OCH₃ —Br C301 q, r, s or t —CF₃ —OCH₃ —F C302 q, r, s or t —CF₃—OCH₃ —CH₃ C303 q, r, s or t —CF₃ —OCH₃ —OCH₃ C304 q, r, s or t —CF₃—OCH₃ —OCH₂CH₃ C305 q, r, s or t —CF₃ —OCH₃ —CF₃ C306 q, r, s or t —CF₃—OCH₃ —OCF₃ C307 q, r, s or t —CF₃ —OCH₃ —CH₂OCH₃ C308 q, r, s or t —CF₃—OCH₃ —C(O)OCH₂CH₃ C309 q, r, s or t —CF₃ —OCH₂CH₃ —H C310 q, r, s or t—CF₃ —OCH₂CH₃ —Cl C311 q, r, s or t —CF₃ —OCH₂CH₃ —Br C312 q, r, s or t—CF₃ —OCH₂CH₃ —F C313q, r, s or t —CF₃ —OCH₂CH₃ —CH₃ C314 q, r, s or t—CF₃ —OCH₂CH₃ —OCH₃ C315 q, r, s or t —CF₃ —OCH₂CH₃ —OCH₂CH₃ C316 q, r,s or t —CF₃ —OCH₂CH₃ —CF₃ C317 q, r, s or t —CF₃ —OCH₂CH₃ —OCF₃ C318 q,r, s or t —CF₃ —OCH₂CH₃ —CH₂OCH₃ C319 q, r, s or t —CF₃ —OCH₂CH₃—C(O)OCH₂CH₃ C320 q, r, s or t —CF₃ —CF₃ —H C321 q, r, s or t —CF₃ —CF₃—Cl C322 q, r, s or t —CF₃ —CF₃ —Br C323 q, r, s or t —CF₃ —CF₃ —F C324q, r, s or t —CF₃ —CF₃ —CH₃ C325 q, r, s or t —CF₃ —CF₃ —OCH₃ C326 q, r,s or t —CF₃ —CF₃ —OCH₂CH₃ C327 q, r, s or t —CF₃ —CF₃ —CF₃ C328 q, r, sor t —CF₃ —CF₃ —OCF₃ C329 q, r, s or t —CF₃ —CF₃ —CH₂OCH₃ C330 q, r, sor t —CF₃ —CF₃ —C(O)OCH₂CH₃ C331 q, r, s or t —CF₃ —OCF₃ —H C332 q, r, sor t —CF₃ —OCF₃ —Cl C333 q, r, s or t —CF₃ —OCF₃ —Br C334 q, r, s or t—CF₃ —OCF₃ —F C335 q, r, s or t —CF₃ —OCF₃ —CH₃ C336 q, r, s or t —CF₃—OCF₃ —OCH₃ C337 q, r, s or t —CF₃ —OCF₃ —OCH₂CH₃ C338 q, r, s or t —CF₃—OCF₃ —CF₃ C339q, r, s or t —CF₃ —OCF₃ —OCF₃ C340 q, r, s or t —CF₃—OCF₃ —CH₂OCH₃ C341 q, r, s or t —CF₃ —OCF₃ —C(O)OCH₂CH₃ C342 q, r, s ort —CF₃ —CH₂OCH₃ —H C343 q, r, s or t —CF₃ —CH₂OCH₃ —Cl C344 q, r, s or t—CF₃ —CH₂OCH₃ —Br C345 q, r, s or t —CF₃ —CH₂OCH₃ —F C346 q, r, s or t—CF₃ —CH₂OCH₃ —CH₃ C347 q, r, s or t —CF₃ —CH₂OCH₃ —OCH₃ C348 q, r, s ort —CF₃ —CH₂OCH₃ —OCH₂CH₃ C349 q, r, s or t —CF₃ —CH₂OCH₃ —CF₃ C350 q, r,s or t —CF₃ —CH₂OCH₃ —OCF₃ C351 q, r, s or t —CF₃ —CH₂OCH₃ —CH₂OCH₃ C352q, r, s or t —CF₃ —CH₂OCH₃ —C(O)OCH₂CH₃ C353 q, r, s or t —CF₃—C(O)OCH₂CH₃ —H C354 q, r, s or t —CF₃ —C(O)OCH₂CH₃ —Cl C355 q, r, s ort —CF₃ —C(O)OCH₂CH₃ —Br C356 q, r, s or t —CF₃ —C(O)OCH₂CH₃ —F C357 q,r, s or t —CF₃ —C(O)OCH₂CH₃ —CH₃ C358 q, r, s or t —CF₃ —C(O)OCH₂CH₃—OCH₃ C359 q, r, s or t —CF₃ —C(O)OCH₂CH₃ —OCH₂CH₃ C360 q, r, s or t—CF₃ —C(O)OCH₂CH₃ —CF₃ C361 q, r, s or t —CF₃ —C(O)OCH₂CH₃ —OCF₃ C362 q,r, s or t —CF₃ —C(O)OCH₂CH₃ —CH₂OCH₃ C363 q, r, s or t —CF₃ —C(O)OCH₂CH₃—C(O)OCH₂CH₃

4.3 Definitions

As used herein, the terms used above having following meaning:“—(C₁-C₄)alkyl” means a straight chain or branched non-cyclichydrocarbon having 1, 2, 3, or 4 carbon atoms. Representative straightchain —(C₁-C₄)alkyls include -methyl, -ethyl, -n-propyl, and -n-butyl.Representative branched —(C₁-C₄)alkyls include -iso-propyl, -sec-butyl,-iso-butyl, and -tert-butyl.

“-Halogen” or “-halo” means —F, —Cl, —Br, or —I.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “2-methyl group”, “2-position methylgroup”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “(R)-2-methyl group”, “(R)-2-positionmethyl group”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “(S)-2-methyl group”, “(S)-2-positionmethyl group”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “3-methyl group”, “3-position methylgroup”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “(R)-3-methyl group”, “(R)-3-positionmethyl group”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the methyl substituent of the piperazine ring of,e.g., compounds of formula (I), “(S)-3-methyl group”, “(S)-3-positionmethyl group”, and the like means

where R₁, R₄, R₈, and R₉ are as defined above for Compounds of Formula(I), where the numbers designate the position of each atom in thepiperazine ring.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (S)configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —CH₃ and the carbon atoms at the a and cpositions of the a-b bond and the c-d bond are each in the (R)configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —CH₃, the carbon atom at the a position of thea-b bond in the (R) configuration, and the carbon atom at the c positionof the c-d bond is in the (S) configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —CH₃, the carbon atom at the a position of thea-b bond in the (S) configuration, and the carbon atom at the c positionof the c-d bond is in the (R) configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (S) configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

In connection with the substituent of the pyridine ring containing R₄,the phrase “wherein R₄ is —H and the carbon atom at the a position ofthe a-b bond is in the (R) configuration” and the like means

where the lower-case letters are used to designate a particular C—O bondin that substituent.

The term “animal,” includes, but is not limited to, a cow, monkey,baboon, chimpanzee, horse, sheep, pig, chicken, turkey, quail, cat, dog,mouse, rat, rabbit, guinea pig, and human.

The phrase “pharmaceutically acceptable derivative”, as used herein,includes any pharmaceutically acceptable salt, polymorph,pseudopolymorph, solvate, co-crystal, prodrug, radiolabeled form,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of a Compoundof Formula (I) of the disclosure.

In one embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate,co-crystal, prodrug, radiolabeled form, stereoisomer, enantiomer,diastereomer, other stereoisomeric form, racemic mixture, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph,pseudopolymorph, solvate, co-crystal, radiolabeled form, stereoisomer,enantiomer, diastereomer, other stereoisomeric form, racemic mixture,geometric isomer, and/or tautomer, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph,pseudopolymorph, solvate, co-crystal, prodrug, stereoisomer, enantiomer,diastereomer, other stereoisomeric form, racemic mixture, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph,pseudopolymorph, solvate, co-crystal, stereoisomer, enantiomer,diastereomer, other stereoisomeric form, racemic mixture, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph, co-crystal,radiolabeled form, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a Compound of Formula (I) of the disclosure. In anotherembodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, polymorph, co-crystal, prodrug,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of a Compoundof Formula (I) of the disclosure. In another embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, polymorph, co-crystal, stereoisomer, enantiomer, diastereomer,other stereoisomeric form, racemic mixture, geometric isomer, and/ortautomer, e.g., of a Compound of Formula (I) of the disclosure. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, co-crystal, radiolabeled form,stereoisomer, enantiomer, diastereomer, other stereoisomeric form,racemic mixture, geometric isomer, and/or tautomer, e.g., of a Compoundof Formula (I) of the disclosure. In another embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, co-crystal, prodrug, stereoisomer, enantiomer, diastereomer, otherstereoisomeric form, racemic mixture, geometric isomer, and/or tautomer,e.g., of a Compound of Formula (I) of the disclosure. In anotherembodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, co-crystal, stereoisomer, enantiomer,diastereomer, other stereoisomeric form, racemic mixture, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure.

In another embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate,co-crystal, radiolabeled form, stereoisomer, geometric isomer, and/ortautomer, e.g., of a Compound of Formula (I) of the disclosure. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate,co-crystal, prodrug, stereoisomer, geometric isomer, and/or tautomer,e.g., of a Compound of Formula (I) of the disclosure. In anotherembodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, polymorph, pseudopolymorph, solvate,co-crystal, stereoisomer, geometric isomer, and/or tautomer, e.g., of aCompound of Formula (I) of the disclosure. In another embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, polymorph, co-crystal, radiolabeled form, stereoisomer, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph, co-crystal,prodrug, stereoisomer, geometric isomer, and/or tautomer, e.g., of aCompound of Formula (I) of the disclosure. In another embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, polymorph, co-crystal, stereoisomer, geometric isomer, and/ortautomer, e.g., of a Compound of Formula (I) of the disclosure. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, co-crystal, radiolabeled form,stereoisomer, geometric isomer, and/or tautomer, e.g., of a Compound ofFormula (I) of the disclosure. In another embodiment, thepharmaceutically acceptable derivative is a pharmaceutically acceptablesalt, co-crystal, prodrug, stereoisomer, geometric isomer, and/ortautomer, e.g., of a Compound of Formula (I) of the disclosure. Inanother embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, co-crystal, stereoisomer, geometricisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, co-crystal,stereoisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, polymorph,stereoisomer, and/or tautomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pharmaceutically acceptable salt, stereoisomer, and/ortautomer, e.g., of a Compound of Formula (I) of the disclosure.

In another embodiment, the pharmaceutically acceptable derivative is apharmaceutically acceptable salt, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a polymorph, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a pseudopolymorph, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a solvate, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a co-crystal, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a prodrug, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a radiolabeled form, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a stereoisomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is an enantiomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a diastereomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a stereoisomeric form other than a stereoisomer, anenantiomer and a diastereomer, e.g., of a Compound of Formula (I) of thedisclosure. In another embodiment, the pharmaceutically acceptablederivative is a racemic mixture, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a geometric isomer, e.g., of a Compound of Formula (I) ofthe disclosure. In another embodiment, the pharmaceutically acceptablederivative is a tautomer, e.g., of a Compound of Formula (I) of thedisclosure.

The phrase “pharmaceutically acceptable salt”, as used herein, is anypharmaceutically acceptable salt that can be prepared from a Compound ofFormula (I) including a salt formed from an acid and a basic functionalgroup, such as a nitrogen group, of a Compound of Formula (I).Illustrative salts include, but are not limited, to sulfate, citrate,acetate, trifluoroacetate, oxalate, chloride, bromide, iodide, nitrate,bisulfate, phosphate, acid phosphate, isonicotinate, lactate,salicylate, acid citrate, tartrate, oleate, tannate, pantothenate,bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate,gluconate, glucoronate, saccharate, formate, benzoate, glutamate,methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate,and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts.The term “pharmaceutically acceptable salt” also includes a saltprepared from a Compound of Formula (I) having an acidic functionalgroup, such as a carboxylic acid functional group, and apharmaceutically acceptable inorganic or organic base. Suitable basesinclude, but are not limited to, hydroxides of alkali metals such assodium, potassium, cesium, and lithium; hydroxides of alkaline earthmetal such as calcium and magnesium; hydroxides of other metals, such asaluminum and zinc; ammonia and organic amines, such as unsubstituted orhydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine;tributyl amine; pyridine; picoline; N-methyl-N-ethylamine; diethylamine;triethylamine; mono-, bis-, or tris-(2-hydroxy-(C₁-C₃)alkyl amines),such as mono-, bis-, or tris-(2-hydroxyethyl)amine,2-hydroxy-tert-butylamine, or tris-(hydroxymethyl)methylamine,N,N-di-[(C₁-C₃)alkyl]-N-(hydroxy-(C₁-C₃)alkyl)-amines, such asN,N-dimethyl-N-(2-hydroxyethyl)amine, or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; and amino acids such as arginine, lysine, and thelike. In one embodiment, the pharmaceutically acceptable salt is ahydrochloride-salt, a sulfate-salt, a sodium-salt, a potassium-salt, abenzene sulfonic acid-salt, a para-toluenesulfonic acid-salt, or afumaric acid-salt. In another embodiment, the pharmaceuticallyacceptable salt is a hydrochloride-salt or a sulfate-salt. In anotherembodiment, the pharmaceutically acceptable salt is ahydrochloride-salt. In another embodiment, the pharmaceuticallyacceptable salt is a sulfate-salt. In another embodiment, thepharmaceutically acceptable salt is a sodium-salt. In anotherembodiment, the pharmaceutically acceptable salt is a potassium-salt. Inanother embodiment, the pharmaceutically acceptable salt is apara-toluenesulfonic acid-salt. In another embodiment, thepharmaceutically acceptable salt is a fumaric acid-salt. In anotherembodiment, the pharmaceutically acceptable fumaric acid-salt containsabout one equivalent of a Compound of Formula (I) and about 0.5equivalents of fumaric acid, e.g., from about 0.3 to about 0.7equivalents of fumaric acid in one embodiment, from about 0.4 to about0.6 equivalents of fumaric acid in another embodiment, from about 0.44to about 0.56 equivalents of fumaric acid in another embodiment, or fromabout 0.47 to about 0.53 equivalents of fumaric acid in anotherembodiment. In another embodiment, the pharmaceutically acceptablefumaric acid-salt contains one equivalent of a Compound of Formula (I)and 0.5 equivalents of fumaric acid. One skilled in the art willrecognize that, e.g., acid addition salts, of a Compound of Formula (I)can be prepared by reaction of the compounds with the appropriate acidby a variety of known methods.

The compounds of the disclosure provided herein also encompass allpolymorphs and pseudopolymorphs of the Compounds of Formula (I).“Polymorphs” are known in the art (see, e.g., Giron, “Investigations ofPolymorphism and Pseudo-polymorphism in Pharmaceuticals by CombinedThermoanalytical Techniques,” J. Thermal Anal. Cal. 64:37-60 (2001)) andare considered to be different crystalline phases in which a Compound ofFormula (I) is capable of existing. The crystalline phases can havedifferent arrangements (“packing polymorphism”) and/or conformations(“conformational polymorphism”) of the molecules in the crystal lattice.For example, in two distinct polymorphs of a Compound of Formula (I),each polymorph can have the molecules arranged in a differentfundamental crystal system—triclinic, monoclinic, orthorhombic,tetragonal, trigonal, hexagonal, or cubic. The term “anhydrate” as usedherein, is any crystalline form of a Compound of Formula (I) in whichwater molecules are a non-integral part of the crystal. An anhydrate ofa Compound of Formula (I) can be prepared, for example, bycrystallization from a solvent substantially free of water. In oneembodiment, the Compound of Formula (I) is present as an anhydrate,i.e., as a free base where the crystal lattice is substantially free ofwater molecules and any water molecules present are present as “surfacewater” (e.g., loosely bound to the crystal's surface) as would bediscernable and distinguishable to those in the art by, e.g.,thermogravimetric analysis (TGA) and/or differential scanningcalorimetry (DSC), from water molecules that are an integral part of thecrystal (e.g., a hydrate). An anhydrate of a Compound of Formula (I) hasless than about 0.2 mole water in one embodiment, less than about 0.15mole water in another embodiment, less than about 0.12 mole water inanother embodiment, less than about 0.1 mole water in anotherembodiment, less than about 0.085 mole water in another embodiment, lessthan about 0.075 mole water in another embodiment, less than about 0.06mole water in another embodiment, less than about 0.057 mole water inanother embodiment, less than about 0.05 mole water in anotherembodiment, less than about 0.03 mole water in another embodiment, lessthan about 0.025 mole water in another embodiment, less than about 0.02mole water in another embodiment, less than about 0.01 mole water inanother embodiment, less than about 0.005 mole water in anotherembodiment, and less than about 0.001 mole water in another embodiment,each said embodiment taking into account the presence of surface waterand each said embodiment being per 1 mole of a Compound of Formula (I).

The compounds of the disclosure provided herein also encompass allsolvates of the Compounds of Formula (I). “Solvates” are known in theart and are considered to be a combination, physical association and/orsolvation of a Compound of Formula (I) with a solvent molecule. Thisphysical association can involve varying degrees of ionic and covalentbonding, including hydrogen bonding. When the solvate is of thestoichiometric type, there is a fixed ratio of the solvent molecule toCompound of Formula (I), e.g., a disolvate, monosolvate or hemisolvatewhen the solvent molecule:Compound of Formula (I) molecule molar ratiois 2:1, 1:1 or 1:2, respectively. In other embodiments, the solvate isof the nonstoichiometric type. For example, the Compound of Formula (I)crystal can contain solvent molecules in the structural voids, e.g.,channels, of the crystal lattice. In certain instances, the solvate canbe isolated, for example when one or more solvent molecules areincorporated into the crystal lattice of a crystalline solid. Thus,“solvate”, as used herein, encompasses both solution-phase andisolatable solvates. As the crystalline form of a solvate can also bereferred to as a “pseudopolymorph”, the compounds of the disclosureprovided herein also encompass all pseudopolymorphs of the Compounds ofFormula (I). A Compound of Formula (I) of the disclosure can be presentas a solvated form with a pharmaceutically acceptable solvent, such aswater, methanol, ethanol, and the like, and it is intended that thedisclosure include both solvated and unsolvated Compound of Formula (I)forms. As “hydrate” relates to a particular subgroup of solvates, i.e.,where the solvent molecule is water, hydrates are included within thesolvates of the disclosure. In one embodiment, the Compound of Formula(I) is present as a monohydrate, i.e., as a free base where thewater:Compound of Formula (I) molar ratio is about 1:1, e.g., from0.91:1 to 1.09:1 in one embodiment, from 0.94:1 to 1.06:1 in anotherembodiment, from 0.97:1 to 1.03:1 in another embodiment, and from0.985:1 to 1.015:1 in another embodiment, each said embodiment taking noaccount of surface water that might be present, if any.

Preparation of solvates is known in the art. For example, Caira et al.,“Preparation and Crystal Characterization of a Polymorph, a Monohydrate,and an Ethyl Acetate Solvate of the Antifungal Fluconazole,” J.Pharmaceut. Sci., 93(3):601-611 (2004), describes the preparation ofsolvates of fluconazole with ethyl acetate and with water. Similarpreparations of solvates, hemisolvate, hydrates, and the like aredescribed by Van Tonder et al., “Preparation and PhysicochemicalCharacterization of 5 Niclosamide Solvates and 1 Hemisolvate,” AAPSPharm. Sci. Tech., 5(1): Article 12 (2004), and Bingham et al., “Overone hundred solvates of sulfathiazole,” Chem. Comm., pp. 603-604 (2001).In one embodiment, a non-limiting, process involves dissolving theCompound of Formula (I) in a desired amount of the desired solvent(organic, water or mixtures thereof) at temperatures above about 20° C.to about 25° C., cooling the solution at a rate sufficient to formcrystals, and isolating the crystals by known methods, e.g., filtration.Analytical techniques, for example, infrared spectroscopy, can be usedto show the presence of the solvent in a crystal of the solvate.

The compounds of the disclosure provided herein also encompass allco-crystals of the Compounds of Formula (I). “Co-crystals” are known inthe art; a co-crystal is considered to be a structurally homogeneouscrystalline material that contains two or more neutral building blocks,e.g., a Compound of Formula (I) with a co-former material, that arepresent in definite stoichiometric amounts. Aakeroy et al., “Co-crystalor Salt: Does it Really Matter?” Mol. Pharmaceutics 4(3):317-322 (2007).As used herein, a “co-crystal” includes all polymorphs of thatco-crystal, i.e., all different crystalline phases of that co-crystal.The main difference between solvates and co-crystals is the physicalstate of the isolated pure components. For, e.g., a two componentsystem, if one component is a liquid at a temperature of about 25° C.then the crystal containing both components is designated as a solvate;if both components are solids at that temperature then the crystalcontaining both components is designated as a co-crystal. Sekhon,“Pharmaceutical Co-crystals—A Review,” Ars. Pharm. 50(3):99-117 (2009).Furthermore, co-crystals and salts can be considered as opposite“extremes” on the scale of the multi-component structures possible.Salts are formed through ionization, e.g., an acid-base reaction orproton donation occurring between the active pharmaceutical ingredientand an acidic or basic substance. In contrast, when the activepharmaceutical ingredient(s) lacks an ionizable site amenable to saltformation, a co-crystal can be formed through unionization, e.g.,hydrogen bonding, π-π, or van der Waals interactions between thecomponents. The differences in structure among a co-crystal, salt, andhydrate are illustrated in, e.g., FIGS. 1 and 2 of Schultheiss et al.,“Pharmaceutical Co-crystals and their Physicochemical Properties,”Crystal Growth & Design 9(6):2950-2967 (2009), which is herebyincorporated by reference. Preparation of co-crystals is known in theart; for example, as described in the above-cited references and in U.S.Pat. Nos. 7,452,555 B2 and 7,935,817 B2.

In one embodiment, a co-crystal with a Compound of Formula (I) compriseshydrochloric acid, tartaric acid, benzenesulfonic acid, toluenesulfonicacid, succinic acid, fumaric acid, citric acid, oxalic acid, benzoicacid, or any mixture thereof. In another embodiment, a co-crystal with aCompound of Formula (I) comprises hydrochloric acid, benzenesulfonicacid, toluenesulfonic acid, L-tartaric acid, fumaric acid, or anymixture thereof. In another embodiment, the co-crystal is of a Compoundof Formula (I) and hydrochloric acid. In another embodiment, theco-crystal is of a Compound of Formula (I) and benzenesulfonic acid. Inanother embodiment, the co-crystal is of a Compound of Formula (I) andtoluenesulfonic acid. In another embodiment, the co-crystal is of aCompound of Formula (I) and L-tartaric acid. In another embodiment, theco-crystal is of a Compound of Formula (I) and fumaric acid. In anotherembodiment, the co-crystal contains about one equivalent of a Compoundof Formula (I) and about 0.5 equivalents of fumaric acid, e.g., fromabout 0.3 to about 0.7 equivalents of fumaric acid in one embodiment,from about 0.4 to about 0.6 equivalents of fumaric acid in anotherembodiment, from about 0.44 to about 0.56 equivalents of fumaric acid inanother embodiment, or from about 0.47 to about 0.53 equivalents offumaric acid in another embodiment. In another embodiment, theco-crystal contains one equivalent of a Compound of Formula (I) and 0.5equivalents of fumaric acid. Analytical techniques, for example,infrared spectroscopy, single crystal x-ray diffraction (XRD), powderx-ray diffraction (PXRD), melting point determination, DSC, differentialthermal analysis (DTA), TGA, solid-state NMR (SSNMR), and x-rayphotoelectron spectroscopy (XPS), can be used to elucidate the structureof a co-crystal. In certain embodiments, XRD, SSNMR, and/or XPS is usedto determine whether a co-crystal or a salt is present. In certainembodiments when a sufficiently large single crystal cannot be grown,SSNMR or XPS is used to determine whether a co-crystal or a salt ispresent.

However, the art recognizes that “the exact classification of a compoundas a salt or a co-crystal can at times be somewhat ambiguous.” Aakeroyet al., at page 321. For example, Aakeroy et al. describe a study wherex-ray and neutron diffraction were used to study hydrogen bondingbetween urotropine N-oxide and formic acid as a function of temperaturein which the exact location of the proton was found to change withtemperature and, under certain conditions, the system displayed partialproton transfer from the acid to the N-oxide moiety, i.e., the systempossessed characteristics intermediate between a salt and a co-crystal.Id. Moreover, Pop et al. describe tiotropium fumarate as,simultaneously, a salt and a co-crystal with a stoichiometry ofcation:anion:co-former of 2:1:1. Pop et al., “Tiotropium Fumarate: AnInteresting Pharmaceutical Co-crystal,” J Pharma. Sci. 98(5):1820-1834(2009). The structure, determined by XRD, is described as “made up oftwo monovalent tiotropium cations combined with a divalent fumarateanion to make the salt, plus a nonionized free fumaric acid moiety tomake the co-crystal.” Id. Thus in connection with the absence of anindisputably clear distinction between a salt and a co-crystal, itshould be understood that the phrase “and combinations thereof”, whenused in the context of a salt and/or a co-crystal, means that acharacteristic attributable to a salt and another characteristicattributable to a co-crystal are simultaneously present in oneembodiment; in another embodiment, a characteristic intermediate betweenthe characteristic attributable to a salt and the characteristicattributable to a co-crystal is present.

The compounds disclosed herein also comprise all prodrugs of theCompounds of Formula (I). “Prodrugs” are known in the art and, while notnecessarily possessing any pharmaceutical activity as such, areconsidered to be any covalently bonded carrier(s) that releases theactive parent drug in vivo. In general, such prodrugs will be afunctional derivative of a Compound of Formula (I) which is readilyconvertible in vivo, e.g., by being metabolized, into the requiredCompound of Formula (I).

Conventional procedures for the selection and preparation of suitableprodrug derivatives are described in, for example, H. Bundgaard ed.,Design of Prodrugs, Elsevier (1985); “Drug and Enzyme Targeting, PartA,” Widder et al., eds., Vol. 112 in Methods in Enzymology, AcademicPress (1985); Bundgaard, “Design and Application of Prodrugs,” Chapter5, pp. 113-191 in A Textbook of Drug Design and Development,Krogsgaard-Larsen and Bundgaard Eds., Harwood Academic Publishers(1991); Bundgaard et al., “(C) Means to Enhance Penetration (1) Prodrugsas a means to improve the delivery of peptide drugs,” Adv. Drug DeliveryRevs. 8:1-38 (1992); Bundgaard et al., “Glycolamide Esters as BiolabileProdrugs of Carboxylic Acid Agents: Synthesis, Stability, Bioconversion,and Physicochemical Properties,” J. Pharmaceut. Sci. 77(4):285-298(1988); and Kakeya et al., “Studies on Prodrugs of Cephalosporins. I.Synthesis and Biological Properties of Glycyloxygenzoyloxymethyl andGlycylaminobenzoyloxymethyl Esters of7β-[2-(2-Aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]3-methyl-3-cephem-4-carboxylicAcid,” Chem. Pharm. Bull. 32:692-698 (1984).

In addition, one or more hydrogen, carbon or other atoms of a Compoundof Formula (I) can be replaced by a radioactive isotope of the hydrogen,carbon or other atoms. Such a “radiolabeled”, “radiolabeled form”, andthe like of a Compound of Formula (I), each of which is encompassed bythe disclosure, is useful as a research and/or diagnostic tool inmetabolism pharmacokinetic studies and in binding assays. “Radioactive”,as used herein with respect to an atom, means an atom that comprises aradioactive atom and therefore the specific radioactivity thereof isabove the background level of radioactivity. Examples of radioactiveisotopes that can be incorporated into a Compound of Formula (I) of thedisclosure include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, chlorine, bromine, and iodine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl,³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I, respectively. In oneembodiment, a radiolabeled Compound of Formula (I) contains 1, 2, 3, 4,or more radioactive isotopes, each of which is independently selectedfrom hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,chlorine, bromine, and iodine. In another embodiment, a radiolabeledCompound of Formula (I) contains 1 or 2 radioactive isotopes, each ofwhich is independently selected from hydrogen, carbon, nitrogen, oxygen,phosphorous, sulfur, fluorine, chlorine, bromine, and iodine. In anotherembodiment, a radiolabeled Compound of Formula (I) contains 1radioactive isotope which is selected from hydrogen, carbon, nitrogen,oxygen, phosphorous, sulfur, fluorine, chlorine, bromine, and iodine. Inanother embodiment, a radiolabeled Compound of Formula (I) contains 1,2, 3, 4, or more radioactive isotopes, each of which is independentlyselected from ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F,¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. Inanother embodiment, a radiolabeled Compound of Formula (I) contains 1 or2 radioactive isotopes, each of which is independently selected from ²H,³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br,⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I. In another embodiment, aradiolabeled Compound of Formula (I) contains 1 radioactive isotopewhich is selected from ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P,³⁵S, ¹⁸F, ¹⁹F, ³⁶Cl, ³⁷Cl, ⁷⁶Br, ⁷⁷Br, ⁸¹Br, ¹²³I, ¹²⁴I, ¹²⁵I, and ¹³¹I.In another embodiment, a radiolabeled Compound of Formula (I) contains1, 2, 3, 4, or more radioactive isotopes, each of which is independentlyselected from ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, and ¹²⁵I. In anotherembodiment, a radiolabeled Compound of Formula (I) contains 1 or 2radioactive isotopes, each of which is independently selected from ³H,¹⁴C, ¹⁵N, ¹⁸O, ³²P, and ¹²⁵I. In another embodiment, a radiolabeledCompound of Formula (I) contains 1 radioactive isotope which is selectedfrom ³H, ¹⁴C, ¹⁵N, ¹⁸O, ³²P, and ¹²⁵I.

Radiolabeled compounds of the disclosure can be prepared by methodsknown in the art. For example, tritiated Compounds of Formula (I) can beprepared by introducing tritium into the particular Compound of Formula(I), for example, by catalytic dehalogenation with tritium. This methodcan include reacting a suitably halogen-substituted precursor of aCompound of Formula (I) with tritium gas in the presence of a suitablecatalyst, for example, Pd/C, in the presence or absence of a base. Othersuitable methods for preparing tritiated compounds can be found inFiler, “The Preparation and Characterization of TritiatedNeurochemicals,” Chapter 6, pp. 155-192 in Isotopes in the Physical andBiomedical Sciences, Vol. 1, Labeled Compounds (Part A) (1987).¹⁴C-labeled compounds can be prepared by employing starting materialshaving a ¹⁴C carbon. Compounds containing piperazine isotopciallyenriched with ¹³C and/or ¹⁵N can be prepared as described in, e.g., FIG.5A and the associated description, of U.S. Pat. No. 7,355,045 B2.

A Compound of Formula (I) can contain one or more asymmetric centers andcan thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms. Unless specifically otherwise indicated, thedisclosure encompasses compounds with all such possible forms as well astheir racemic and resolved forms or any mixture thereof. When a Compoundof Formula (I) contains an olefinic double bond or other center ofgeometric asymmetry, and unless specifically otherwise indicated, it isintended to include all “geometric isomers”, e.g., both E and Zgeometric isomers. Unless specifically otherwise indicated, all“tautomers”, e.g., ketone-enol, amide-imidic acid, lactam-lactim,enamine-imine, amine-imine, and enamine-enimine tautomers, are intendedto be encompassed by the disclosure as well.

As used herein, the terms “stereoisomer”, “stereoisomeric form”, and thelike are general terms for all isomers of individual molecules thatdiffer only in the orientation of their atoms in space. It includesenantiomers and isomers of compounds with more than one chiral centerthat are not mirror images of one another (“diastereomers”).

The term “chiral center” refers to a carbon atom to which four differentgroups are attached.

The term “enantiomer” or “enantiomeric” refers to a molecule that isnonsuperimposeable on its mirror image and hence optically active wherethe enantiomer rotates the plane of polarized light in one direction andits mirror image rotates the plane of polarized light in the oppositedirection.

The term “racemic” refers to a mixture of equal parts of enantiomerswhich is optically inactive.

The term “resolution” refers to the separation or concentration ordepletion of one of the two enantiomeric forms of a molecule. Opticalisomers of a Compound of Formula (I) can be obtained by known techniquessuch as chiral chromatography or formation of diastereomeric salts froman optically active acid or base.

Optical purity can be stated in terms of enantiomeric excess (% ee),which is determined by the formula:

${\%\mspace{14mu}{ee}} = {\left\lbrack \frac{{{major}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})} - {{minor}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})}}{{{major}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})} + {{minor}\mspace{14mu}{enantiomer}\mspace{14mu}({mol})}} \right\rbrack \times 100\mspace{11mu}{\%.}}$

The term “MeOH” means methanol, i.e., methyl alcohol.

The term “EtOH” means ethanol, i.e., ethyl alcohol.

The term “t-BuOH” means tert-butyl alcohol, i.e., 2-methylpropan-2-ol.

The term “THF” means tetrahydrofuran.

The term “DMF” means N,N-dimethylformamide.

The term “DCM” means methylene chloride, i.e., dichloromethane.

The term “DCE” means dichloroethane.

The term “DME” means 1,2-dimethoxyethane, i.e., ethylene glycol dimethylether.

The term “EtOAc” means ethyl acetate.

The term “NH₄OH” means ammonium hydroxide.

The term “TEA” means triethylamine.

The term “MeCN” means acetonitrile.

The term “NaH” means sodium hydride.

The term “AcOH” means acetic acid.

The term “DMSO” means dimethylsulfoxide, i.e., methylsulfinylmethane.

The term “DIEA” means diisopropylethylamine, i.e.,N-ethyl-N-isopropylpropan-2-amine.

The term “BuLi” means butyl lithium.

The term “BOC” means tert-butyloxycarbonyl:

The term “HOBT” means 1-hydroxybenzotriazole hydrate.

The term “EDCI” means 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide.

The term “IBD” means inflammatory-bowel disease.

The term “IBS” means irritable-bowel syndrome.

The term “ALS” means amyotrophic lateral sclerosis.

The phrase “effective amount,” when used in connection with a Compoundof Formula (I) means an amount effective for: (a) treating or preventinga Condition or symptom thereof; (b) detectably inhibiting TRPV1 receptorfunction in a cell, or (c) detectably activating TRPV1 receptor functionin a cell.

The phrase “effective amount,” when used in connection with an othertherapeutic agent or a second therapeutic agent means an amount forproviding the therapeutic effect of the second therapeutic agent.

The phrase “therapeutic index,” describes the gap between the dose thatis effective, and the dose that induces adverse effects.

The terms “modulate”, “modulating”, and the like as used herein withrespect to the TRPV1 receptor mean the mediation of a pharmacodynamicresponse (e.g., analgesia) in an animal from (i) inhibiting oractivating the receptor, or (ii) directly or indirectly affecting thenormal regulation of the receptor activity. Compounds that modulate thereceptor activity include agonists, partial agonists, antagonists, mixedagonists/antagonists, mixed partial agonists/antagonists and compoundswhich directly or indirectly affect regulation of the receptor activity.

As used herein, a compound that binds to a receptor and mimics theregulatory effect(s) of an endogenous ligand is defined as an “agonist”.As used herein, a compound that binds to a receptor and is only partlyeffective as an agonist is defined as a “partial agonist”. As usedherein, a compound that binds to a receptor but produces no regulatoryeffect, but rather blocks binding of another agent to the receptor isdefined as an “antagonist”. (See Ross and Kenakin, Pharmacodynamics:Mechanisms of Drug Action and the Relationship Between DrugConcentration and Effect, Chapter 2 in Goodman & Gilman's ThePharmacological Basis of Therapeutics 31-32 (Hardman et al., eds.,10^(th) ed. 2001).

The phrases “treatment of,” “treating” and the like include theamelioration or cessation of a Condition or a symptom thereof. In oneembodiment, treating includes inhibiting, for example, decreasing theoverall frequency of episodes of a Condition or a symptom thereof.

The phrases “prevention of,” “preventing” and the like include theavoidance of the onset of a Condition or a symptom thereof.

A “disorder” includes, but is not limited to, the Conditions definedabove.

In the event of doubt as to the agreement of a depicted chemicalstructure and a chemical name, the depicted chemical structure governs.

It is appreciated that various features of the disclosure which are, forclarity, described in the context of separate embodiments, can also beprovided in combination in a single embodiment unless otherwisespecifically herein excluded. Conversely, various features of thedisclosure which are, for brevity, described in the context of a singleembodiment, can also be provided separately and/or in any suitablesubcombination unless otherwise specifically herein excluded.

4.4 Methods for Making Compounds of Formula (I)

The Compounds of Formula (I) can be made using conventional organicsynthesis or by the illustrative methods shown in the Schemes below.

4.4.1 Methods for Installing a Vinyl Group on Substituted Pyridine

4.4.1.1 Suzuki Coupling

The introduction of a vinyl group by a Suzuki cross-coupling reaction isexemplified in Scheme 1 below, where R₁ and R₄ are as defined above, Lis a -halo, and each R₅ is independently selected from —(C₁-C₄)alkyl orboth R (groups together form a —CH₂—CH₂— or a —CH₂—CH₂—CH₂— grouplinking each oxygen atom and the boron atom to which they are attachedinto a ring, which ring can be optionally substituted by one or more—CH₃ groups.

In one embodiment, the leaving groups (L) at the 2-position and5-position on the pyridine ring of a compound of formula 1 can beselected to be the same halogen atom, e.g., each is bromine, or, inanother embodiment, can be selected to be different halogen atoms. Forexample, the leaving group in the 2-position of the pyridine ring of thecompound of formula 1 can be —Cl while the leaving group in the5-position of the pyridine ring can be —Br. Examples of boronate esters2 include, but are not limited to,4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane,4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane, and di-n-butyl vinylboronic ester. The reaction is carried out in a suitable organic solvent(e.g., THF or DMF) in the presence of an excess oftetra(n-butyl)ammonium fluoride (TBAF). In an alternative embodiment,CsF can be used instead of TBAF. Examples of palladium catalystsinclude, but are not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(DPPF)Cl₂) and bis(triphenylphosphine)dichloropalladium(II)(Pd(PPh₃)₂Cl₂). The reaction can be carried out in the presence of abase, such as potassium carbonate. The compounds of formula 1 arecommercially available or can be prepared by procedures known in theart.

4.4.1.2 Oxidation Followed by Wittig Olefination

An alternative technique for installation of a vinyl group is shown inScheme 2 below, where R₁ and L are as defined above

The first step involves the oxidation of an alcohol group of thecompound of formula 4 to an aldehyde, thereby producing a compound offormula 5. The aldehyde group of the compound of formula 5 is thenconverted into a vinyl group by a Wittig olefination reaction to providethe compound of formula 6. The compounds of formula 4 are commerciallyavailable or can be prepared by procedures known in the art.

4.4.1.3 Reduction Followed by Dehydration

An alternative technique for installation of a vinyl group is shown inScheme 3 below, where R₁, R₄, and L are as defined above.

The first step involves the reduction of the ketone group of thecompound of formula 7 to the hydroxyl group of a compound of formula 8.Following addition of p-toluene sulfonic acid, the compound of formula 8is dehydrated to produce a compound of formula 3. The compounds offormula 7 are commercially available or can be prepared by proceduresknown in the art.

4.4.2 Methods for Preparing Diols

4.4.2.1 Asymmetric Dihydroxylation of Vinyl Substituted Pyridines

Asymmetric dihydroxylation can be carried out as illustrated in Scheme 4below, where a compound of formula 3 is shown as the starting materialand where R₁, R₄, and L are as defined above. The compound of formula 6could also serve as the starting material in Scheme 4.

As demonstrated in Scheme 4, the stereochemistry of the resulting dioldepends upon the chirality of the ligand used in the AD mix as describedin, e.g., Sharpless et al., J. Org. Chem. 57:2768-2771 (1992) andSchemes 1.14 and 1.15 of U.S. Patent Application Publication No.2009/0170868 A1. AD-mix is composed of the following components:potassium osmate (K₂OsO₂(OH)₄), potassium ferricyanide (K₃Fe(CN)₆),potassium carbonate (K₂CO₃), and the chiral ligands as shown in Scheme5. In one embodiment, the reaction produces a chiral diol having anenantiomeric excess (ee) of at least about 80%. In another embodiment,the reaction produces a chiral diol having a % ee of at least about 90%.In another embodiment, the reaction produces a chiral diol having a % eeof at least about 93%. In another embodiment, the reaction produces achiral diol having a % ee of at least about 94%. In another embodiment,the reaction produces a chiral diol having a % ee of at least about 95%.In another embodiment, the reaction produces a chiral diol having a % eeof greater than 95% (e.g., 95.1% to 99.9%). In another embodiment, thereaction produces a chiral diol having a % ee of at least about 96%. Inanother embodiment, the reaction produces a chiral diol having a % ee ofgreater than 96% (e.g., 96.1% to 99.9%). In another embodiment, thereaction produces a chiral diol having a % ee of at least about 97%. Inanother embodiment, the reaction produces a chiral diol having a % ee ofgreater than 97% (e.g., 97.1% to 99.9%).

4.4.2.2 Preparation of Chiral Diols Via Weinreb Amides

Diastereomers of the compounds of formulas 10a and 10b can be preparedby an alternative synthetic route. An example of such an alternativeroute is depicted in Schemes 6-10, below. A Weinreb amide of formula 14is first prepared by conventional means, as shown in Scheme 6.

In Scheme 6, protection of the hydroxyl group of the compound of formula11 with a tert-butyldimethylsilyl (TBS) group followed by hydrolysisprovides a compound of formula 12. Reaction of a compound of formula 12with a compound of formula 13 (where WSC is1-(3-(dimethylamino)propyl-3-ethyl-carbodiimide) provides a compound offormula 14. The compounds of formulae 11 and 13 are commerciallyavailable or can be prepared by procedures known in the art.

The compound of formula 14 is then reacted with a compound of formula 1in the presence of iso-propylmagnesium chloride and lithium chloride toproduce a compound of formula 15, as shown in Scheme 7, where R₁ and Lare as defined above.

Diastereoselective reduction of the compound of formula 15 with theorganoborane reducing agent L-selectride produces a compound of formula16, as shown in Scheme 8.

The reaction is preferentially carried out in a mixed solvent systemsuch as hexane/THF at a low temperature (e.g., −78° C.).

The compound of formula 16 is then reacted with 4-nitrobenzoic acid inthe presence of triphenylphosphine and diethyl azodicarboxylate (DEAD)to produce a compound of formula 17, as shown in Scheme 9.

Basic hydrolysis of the compound of formula 17 followed by removal ofthe TBS group provides a compound of formula 10c′ as shown in Scheme 10,where the “prime” suffix (“′”) denotes that R₄ is —CH₃. The enantiomericexcess (ee) of the compound of formula 10c′ is at least about 80% and/orthe % ee values as set forth above with respect to Scheme 4.

It will be appreciated that when the enantiomer of the compound offormula 11 (see Scheme 6), i.e., compound 11a, is used as a startingmaterial, then the enantiomer of the compound of formula 10c′, i.e.,compound 10d′, is produced as shown in Scheme 11 by following the stepsas depicted in Schemes 6-10.

The enantiomeric excess (ee) of the compound of formula 10d′ is at leastabout 80% and/or the % ee values as set forth above with respect toScheme 4. The compounds of formula 11 a are commercially available orcan be prepared by procedures known in the art.

4.4.2.3 Preparation of Racemic Diols

Racemic diols can be prepared by methods known in the art using osmiumtetroxide (OsO₄) and N-methyl morpholine N-oxide (NMO) in an aqueousacetone solution.

4.4.3 Methods for Coupling Substituted Pyridines to Piperazines

A compound of formula 18 can be prepared by addition of a compound offormula 10 to a compound of formula 19 in the presence of a palladiumcatalyst, as depicted in Scheme 12, where R₁, R₄, m, and L are asdefined above.

It will be appreciated that in accordance with the disclosure, thecompound of formula 19 has one of the following structures:

The compounds of formula 19 are commercially available or can beprepared by procedures known in the art. It will be further appreciatedthat the compound of formula 19 can be reacted with a compound offormula 10a, 10b, 10c′, or 10d′ to produce a compound of formula 18a,18b, 18c′, or 18d′, respectively.

In an alternative embodiment, the compound of formula 18 can be obtainedas shown in Scheme 13, where R₁, R₄, m, and L are as defined above andP_(N) is a nitrogen protecting group (e.g., BOC).

In this embodiment, the hydroxyl groups of the compound of formula 10are protected to provide a compound of formula 20 prior to coupling thecompound of formula 20 to the compound of formula 21. Such protection isaccomplished through the addition to the compound of formula 10 of2,2-dimethoxypropane in the presence of para-toluene sulfonic acidmonohydrate (PTSA) to provide the compound of formula 20. The compoundof formula 20 is then reacted with a compound of formula 21 in thepresence of a palladium catalyst and a base to provide a compound offormula 22. The compound of formula 22 is then reacted with an excess ofacid, e.g., HCl, to provide the deprotected compound of formula 18. Itwill be appreciated that in accordance with the disclosure, the compoundof formula 21 has one of the following structures:

The compounds of formula 21 are commercially available or can beprepared by procedures known in the art. It will be further appreciatedthat the compound of formula 10 can be replaced with the compound offormula 10a, 10b, 10c′, or 10d′ in Scheme 13 to produce a compound offormula 18a, 18b, 18c′, or 18d′, respectively. In these embodiments, theenantiomeric excess (ee) of the compound of formula 18a (or 18b or 18c′or 18d′) is at least about 80% and/or the % ee values as set forth abovewith respect to Scheme 4.

4.4.4 Methods for Preparing Benzothiazol-2-Amines of Formula 23

A compound of formula 23 can be prepared by the addition of potassiumthiocyanate, bromine, and acetic acid to a compound of formula 24 asdepicted in Scheme 14, where R₈ and R₉ are as defined above. Thecompound of formula 23 is precipitated from solution following theaddition of ammonium hydroxide. The compounds of formula 24 arecommercially available or can be prepared by procedures known in theart.

4.4.5 Methods for Preparing Carboxamides of Formula 26

A compound of formula 26 can be prepared by adding a compound of formula23 to a compound of formula 25 in the presence of a base, such as TEA orDIEA, as depicted in Scheme 15, where R₁, R₄, R₈, R₉, and m are asdefined above and each L₂ is a leaving group independently selected fromphenyl, 4-nitrophenyl, and imidazol-1-yl. The compounds of formula 25are commercially available or can be prepared by procedures known in theart.

4.4.6 Methods for Preparing Piperazine Derivatives of Formula (I)

A Compound of Formula (I) can be prepared by adding a compound ofFormula 26 to a compound of formula 18 as depicted in Scheme 16, whereR₁, R₄, R₈, R₉, m, and L₂ are as defined above.

In certain embodiments, the reaction is carried out in DCM or an aproticorganic solvent. In certain embodiments, a compound of formula 18a, 18b,18c′, or 18d′ is treated with a compound of formula 26 to produce anenantiomerically enriched diol, as exemplified in non-limiting Scheme 17for a compound of formula 18a, where R₁, R₄, R₈, R₉, m, and L₂ are asdefined above. In these embodiments, the enantiomeric excess (ee) of theCompound of Formula (I) is at least about 80%. In another embodiment,the reaction produces a Compound of Formula (I) having a % ee of atleast about 90%. In another embodiment, the reaction produces a Compoundof Formula (I) having a % ee of at least about 93%. In anotherembodiment, the reaction produces a Compound of Formula (I) having a %ee of at least about 94%. In another embodiment, the reaction produces aCompound of Formula (I) having a % ee of at least about 95%. In anotherembodiment, the reaction produces a Compound of Formula (I) having a %ee of greater than 95% (e.g., 95.1% to 99.9%). In another embodiment,the reaction produces a Compound of Formula (I) having a % ee of atleast about 96%. In another embodiment, the reaction produces a Compoundof Formula (I) having a % ee of greater than 96% (e.g., 96.1% to 99.9%).In another embodiment, the reaction produces a Compound of Formula (I)having a % ee of at least about 97%. In another embodiment, the reactionproduces a Compound of Formula (1) having a % ee of greater than 97%(e.g., 97.1% to 99.9%).

It will be appreciated that alternative methods can be used to prepareCompounds of Formula (I). For example, as shown in Scheme 18 a compoundof formula 3 can be added to a compound of formula 21 to produce acompound of formula 27, e.g., by the method of step 2 of Scheme 13,where R₁, R₄, m, and P_(N) are as defined above.

The compound of formula 27 is then dihydroxylated, e.g., by the methodof Scheme 4, Schemes 6-10, or Scheme 11, to produce a compound offormula 28 as shown in Scheme 19, where R₁, R₄, m, and P_(N) are asdefined above.

For example, the reaction depicted in Scheme 19 can be carried out inenantioselective manner using reaction conditions described in Scheme 4.Alternatively, a racemic diol can be prepared by methods known in theart using osmium tetroxide (OsO₄) and N-methyl morpholine N-oxide (NMO)in an aqueous acetone solution.

As depicted in Scheme 20, where R₁, R₄, R₈, R₉, m, P_(N), and L₂ are asdefined above, the compound of formula 28 is deprotected with an excessof acid, e.g., HCl, to provide a compound of formula 18, e.g., by themethod of step 3 of Scheme 13. Reaction of the compound of formula 18with a compound of formula 26 in the presence of a base (see, e.g.,Schemes 16 and 17) provides a Compound of Formula (I).

The progress of the reaction(s) above can be monitored usingconventional analytical techniques including, but not limited to, highpressure liquid chromatography (HPLC), column chromatography, thin-layerchromatography (TLC), gas chromatography (GC), mass spectrometry (MS),and nuclear magnetic resonance spectroscopy (NMR) such as ¹H NMR and ¹³CNMR. Compounds of Formula (I) can be isolated and further treated ifdesired. In one embodiment, the Compound of Formula (I) is isolated byremoving the solvent under reduced pressure. In another embodiment, theCompound of Formula (I) is isolated by extraction. Compounds of Formula(I) can be further treated, for example, by column chromatography orrecrystallization.

Suitable aprotic organic solvents for use in the illustrative methodsinclude, but are not limited to, DCM, DMSO, chloroform, toluene,benzene, acetonitrile, carbon tetrachloride, pentane, hexane, ligroin,and diethyl ether. In one embodiment, the aprotic organic solvent isDCM.

One or more hydrogen, carbon, or other atom(s) of a Compound of Formula(I) can be replaced by an isotope of the hydrogen, carbon, or otheratom(s). Such compounds, which are encompassed by the disclosure, areuseful, e.g., as research and diagnostic tools in metabolismpharmacokinetic studies and in binding assays.

4.5 Therapeutic Uses of Compounds of Formula (I)

In accordance with the disclosure, the Compounds of Formula (I) areadministered to an animal in need of treatment or prevention of aCondition.

In one embodiment, an effective amount of a Compound of Formula (I) canbe used to treat or prevent any condition treatable or preventable byinhibiting TRPV1. Examples of Conditions that are treatable orpreventable by inhibiting TRPV1 include, but are not limited to, pain,e.g., pain associated with osteoarthritis, osteoarthritis, UI, an ulcer,IBD, and/or IBS.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent acute or chronicpain. Examples of pain that can be treated or prevented using a Compoundof Formula (I) include, but are not limited to, cancer pain, neuropathicpain, labor pain, myocardial infarction pain, pancreatic pain, colicpain, post-operative pain, headache pain, muscle pain, arthritic pain,and pain associated with a periodontal disease, including gingivitis andperiodontitis.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can also be used for treating or preventing painassociated with inflammation or with an inflammatory disease in ananimal. Such pain can arise where there is an inflammation of the bodytissue which can be a local inflammatory response and/or a systemicinflammation. For example, the Compounds of Formula (I) can be used totreat or prevent pain associated with inflammatory diseases including,but not limited to: organ transplant rejection; reoxygenation injuryresulting from organ transplantation (see Grupp et al., “Protectionagainst Hypoxia-reoxygenation in the Absence of Poly (ADP-ribose)Synthetase in Isolated Working Hearts,” J. Mol. Cell Cardiol. 31:297-303(1999)) including, but not limited to, transplantation of the heart,lung, liver, or kidney; chronic inflammatory diseases of the joints,including arthritis, rheumatoid arthritis, osteoarthritis and bonediseases associated with increased bone resorption; inflammatory boweldiseases, such as ileitis, ulcerative colitis, Barrett's syndrome, andCrohn's disease; inflammatory lung diseases, such as asthma, adultrespiratory distress syndrome, and chronic obstructive airway disease;inflammatory diseases of the eye, including corneal dystrophy, trachoma,onchocerciasis, uveitis, sympathetic ophthalmitis and endophthalmitis;chronic inflammatory diseases of the gum, including gingivitis andperiodontitis; tuberculosis; leprosy; inflammatory diseases of thekidney, including uremic complications, glomerulonephritis andnephrosis; inflammatory diseases of the skin, includingsclerodermatitis, psoriasis and eczema; inflammatory diseases of thecentral nervous system, including chronic demyelinating diseases of thenervous system, multiple sclerosis, AIDS-related neurodegeneration andAlzheimer s disease, infectious meningitis, encephalomyelitis,Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosisand viral or autoimmune encephalitis; autoimmune diseases, includingType I and Type II diabetes mellitus; diabetic complications, including,but not limited to, diabetic cataract, glaucoma, retinopathy,nephropathy (such as microalbuminuria and progressive diabeticnephropathy), polyneuropathy, mononeuropathies, autonomic neuropathy,gangrene of the feet, atherosclerotic coronary arterial disease,peripheral arterial disease, nonketotic hyperglycemic-hyperosmolar coma,foot ulcers, joint problems, and a skin or mucous membrane complication(such as an infection, a shin spot, a candidal infection or necrobiosislipoidica diabeticorum); immune-complex vasculitis, and systemic lupuserythematosus (SLE); inflammatory diseases of the heart, such ascardiomyopathy, ischemic heart disease hypercholesterolemia, andatherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma, and cancer. The Compoundsof Formula (I) can also be used for inhibiting, treating, or preventingpain associated with inflammatory disease that can, for example, be asystemic inflammation of the body, exemplified by gram-positive or gramnegative shock, hemorrhagic or anaphylactic shock, or shock induced bycancer chemotherapy in response to pro-inflammatory cytokines, e.g.,shock associated with pro-inflammatory cytokines. Such shock can beinduced, e.g., by a chemotherapeutic agent that is adminstered as atreatment for cancer.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can also be used to treat or prevent pain associatedwith nerve injury (i.e., neuropathic pain). Chronic neuropathic pain isa heterogenous disease state with an unclear etiology. In chronicneuropathic pain, the pain can be mediated by multiple mechanisms. Thistype of pain generally arises from injury to the peripheral or centralnervous tissue. The syndromes include pain associated with spinal cordinjury, multiple sclerosis, post-herpetic neuralgia, trigeminalneuralgia, phantom pain, causalgia, and reflex sympathetic dystrophy andlower back pain. The chronic pain is different from acute pain in thatchronic neuropathic pain patients suffer the abnormal pain sensationsthat can be described as spontaneous pain, continuous superficialburning and/or deep aching pain. The pain can be evoked by heat-, cold-,and mechano-hyperalgesia, or by heat-, cold-, or mechano-allodynia.

Chronic neuropathic pain can be caused by injury or infection ofperipheral sensory nerves. It includes, but is not limited to, pain fromperipheral nerve trauma, herpes virus infection, diabetes mellitus,causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis.Neuropathic pain can also be caused by nerve damage from chronicalcoholism, human immunodeficiency virus infection, hypothyroidism,uremia, or vitamin deficiencies. Stroke (spinal or brain) and spinalcord injury can also induce neuropathic pain. Cancer-related neuropathicpain results from tumor growth compression of adjacent nerves, brain, orspinal cord. In addition, cancer treatments, including chemotherapy andradiation therapy, can cause nerve injury. Neuropathic pain includes butis not limited to pain caused by nerve injury such as, for example, thepain from which diabetics suffer.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent a migraineincluding, but not limited to, migraine without aura (“commonmigraine”), migraine with aura (“classic migraine”), migraine withoutheadache, basilar migraine, familial hemiplegic migraine, migrainousinfarction, and migraine with prolonged aura.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent pain associated withosteoarthritis. Osteoarthritis (OA), also known as osteoarthrosis,degenerative arthritis, or degenerative joint disease, is a group ofmechanical abnormalities involving degradation of joints, includingarticular cartilage and subchondral bone. Examples of OA treatable orpreventable using the Compounds of Formula (I) include, but are notlimited to, joint pain, joint stiffness, joint tenderness, jointlocking, and joint effusion.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent UI. Examples of UItreatable or preventable using the Compounds of Formula (I) include, butare not limited to, urge incontinence, stress incontinence, overflowincontinence, neurogenic incontinence, and total incontinence.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent an ulcer. Examplesof ulcers treatable or preventable using the Compounds of Formula (I)include, but are not limited to, a duodenal ulcer, a gastric ulcer, amarginal ulcer, an esophageal ulcer, or a stress ulcer.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent IBD, includingCrohn's disease and ulcerative colitis.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be used to treat or prevent IBS. Examples of IBStreatable or preventable using the Compounds of Formula (I) include, butare not limited to, spastic-colon-type IBS and constipation-predominantIBS.

Applicants believe that the Compounds of Formula (I), or apharmaceutically acceptable derivative thereof, are antagonists forTRPV1. The disclosure also relates to methods for inhibiting TRPV1function in a cell comprising contacting a cell capable of expressingTRPV1 with an effective amount of a Compound of Formula (I), or apharmaceutically acceptable derivative thereof. This method can be usedin vitro, for example, as an assay to select cells that express TRPV1and, accordingly, are useful as part of an assay to select compoundsuseful for treating or preventing pain, e.g., pain associated withosteoarthritis, osteoarthritis, UI, an ulcer, IBD, or IBS. The method isalso useful for inhibiting TRPV1 function in a cell in vivo, in ananimal, a human in one embodiment, by contacting a cell, in an animal,with an effective amount of a Compound of Formula (I), or apharmaceutically acceptable derivative thereof. In one embodiment, themethod is useful for treating or preventing pain in an animal. Inanother embodiment, the method is useful for treating or preventing UIin an animal. In another embodiment, the method is useful for treatingor preventing an ulcer in an animal. In another embodiment, the methodis useful for treating or preventing IBD in an animal. In anotherembodiment, the method is useful for treating or preventing IBS in ananimal.

Examples of tissue comprising cells capable of expressing TRPV1 include,but are not limited to, neuronal, brain, kidney, urothelium, and bladdertissue. Methods for assaying cells that express TRPV1 are known in theart.

4.6 Therapeutic/Prophylactic Administration and Compositions of theDisclosure

Due to their activity, Compounds of Formula (I), or a pharmaceuticallyacceptable derivative thereof, are advantageously useful in veterinaryand human medicine. As described above, Compounds of Formula (I), or apharmaceutically acceptable derivative thereof, are useful for treatingor preventing a Condition.

When administered to an animal, Compounds of Formula (I), or apharmaceutically acceptable derivative thereof, are, in one embodiment,administered as a component of a composition that comprises apharmaceutically acceptable carrier or excipient. The compositions,which comprise a Compound of Formula (I), or a pharmaceuticallyacceptable derivative thereof, can be administered orally. Compounds offormula (I), or a pharmaceutically acceptable derivative thereof, canalso be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral, rectal, and intestinal mucosa, etc.)and can be administered together with another therapeutically activeagent. Administration can be systemic or local. Various delivery systemsare known, e.g., encapsulation in liposomes, microparticles,microcapsules, capsules, etc., and can be used to administer theCompound of Formula (I), or a pharmaceutically acceptable derivativethereof.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectal, by inhalation, or topical, particularly to the ears, nose, eyes,or skin. The mode of administration is left to the discretion of thepractitioner. In most instances, administration will result in therelease of Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, into the bloodstream.

In specific embodiments, it can be desirable to administer the Compoundsof Formula (I), or a pharmaceutically acceptable derivative thereof,locally. This can be achieved, for example, and not by way oflimitation, by local infusion during surgery, topical application, e.g.,in conjunction with a wound dressing after surgery, by injection, bymeans of a catheter, by means of a suppository or enema, or by means ofan implant, said implant being of a porous, non-porous, or gelatinousmaterial, including membranes, such as sialastic membranes, or fibers.

In certain embodiments, it can be desirable to introduce the Compoundsof Formula (I), or a pharmaceutically acceptable derivative thereof,into the central nervous system or gastrointestinal tract by anysuitable route, including intraventricular, intrathecal, and epiduralinjection, and enema. Intraventricular injection can be facilitated byan intraventricular catheter, for example, attached to a reservoir, suchas an Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the Compounds of Formula (I) can be formulated as asuppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the Compounds of Formula (I), or apharmaceutically acceptable derivative thereof, can be delivered in avesicle, in particular a liposome (see Langer, “New Methods of DrugDelivery,” Science 249:1527-1533 (1990); Lopez-Berestein, “Treatment ofSystemic Fungal Infections with Liposomal-Amphotericin B,” Liposomes inthe Therapy of Infectious Disease and Cancer, pp. 317-327 (1989); andTreat et al., “Liposome encapsulated doxorubicin—preliminary results ofphase I and phase II trials” Liposomes in the Therapy of InfectiousDisease and Cancer, pp. 353-365 (1989).

In yet another embodiment, the Compounds of Formula (I), or apharmaceutically acceptable derivative thereof, can be delivered in acontrolled-release system or sustained-release system (see, e.g.,Goodson, “Dental Applications,” pp. 115-138 in Medical Applications ofControlled Release, Vol. 2, Applications and Evaluation, Langer andWise, eds., CRC Press (1984), hereafter “Goodson”). Other controlled- orsustained-release systems discussed in the review by Langer, Science249:1527-1533 (1990) can be used. In one embodiment, a pump can be used(Langer, Science 249:1527-1533 (1990); Sefton, “Implantable Pumps,” inCRC Crit. Rev. Biomed. Eng. 14(3):201-240 (1987); Buchwald et al.,“Long-term, Continuous Intravenous Heparin Administration by anImplantable Infusion Pump in Ambulatory Patients with Recurrent VenousThrombosis,” Surgery 88:507-516 (1980); and Saudek et al., “APreliminary Trial of the Programmable Implantable Medication System forInsulin Delivery,” New Engl. J Med. 321:574-579 (1989)). In anotherembodiment, polymeric materials can be used (see Goodson; Smolen et al.,“Drug Product Design and Performance,” Controlled Drug BioavailabilityVol. 1, John Wiley & Sons, New York (1984); Langer et al., “Chemical andPhysical Structure of Polymers as Carriers for Controlled Release ofBioactive Agents: A Review,” J. Macromol. Sci. Rev. Macromol. Chem.C23(1):61-126 (1983); Levy et al., “Inhibition of Calcification ofBioprosthetic Heart Valves by Local Controlled-Release Diphosphonate,”Science 228:190-192 (1985); During et al., “Controlled Release ofDopamine from a Polymeric Brain Implant: In Vivo Characterization,” Ann.Neurol. 25:351-356 (1989); and Howard et al., “Intracerebral drugdelivery in rats with lesion-induced memory deficits,” J. Neurosurg.71:105 (1989)). In yet another embodiment, a controlled- orsustained-release system can be placed in proximity of a target of theCompounds of Formula (I), e.g., the spinal column, brain, orgastrointestinal tract, thus requiring only a fraction of the systemicdose.

The compositions can optionally comprise a suitable amount of apharmaceutically acceptable excipient so as to provide the form forproper administration to the animal. Such a pharmaceutical excipient canbe a diluent, suspending agent, solubilizer, binder, disintegrant,preservative, coloring agent, lubricant, and the like. Thepharmaceutical excipient can be a liquid, such as water or an oil,including those of petroleum, animal, vegetable, or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.The pharmaceutical excipient can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening, lubricating, and coloring agents canbe used. In one embodiment, the pharmaceutically acceptable excipient issterile when administered to an animal. Water is a particularly usefulexcipient when a Compound of Formula (I) is administered intravenously.Saline solutions and aqueous dextrose and glycerol solutions can also beemployed as liquid excipients, particularly for injectable solutions.Suitable pharmaceutical excipients also include starch, glucose,lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodiumstearate, glycerol monostearate, talc, sodium chloride, dried skim milk,glycerol, propylene glycol, water, ethanol, and the like. Thecompositions, if desired, can also contain minor amounts of wetting oremulsifying agents, or pH buffering agents. Specific examples ofpharmaceutically acceptable carriers and excipients that can be used toformulate oral dosage forms are described in the Handbook ofPharmaceutical Excipients, (Amer. Pharmaceutical Ass'n, Washington,D.C., 1986), incorporated herein by reference.

The compositions can take the form of solutions, suspensions, emulsion,tablets, pills, pellets, multiparticulates, capsules, capsulescontaining liquids, powders, multiparticulates, sustained-releaseformulations, suppositories, emulsions, aerosols, sprays, suspensions,or any other form suitable for use. In one embodiment, the compositionis in the form of a capsule (see e.g., U.S. Pat. No. 5,698,155). Otherexamples of suitable pharmaceutical excipients are described byRadebough et al., “Preformulation,” pp. 1447-1676 in Remington'sPharmaceutical Sciences Vol. 2 (Gennaro, ed., 19^(th) ed., MackPublishing, Easton, Pa., 1995), incorporated herein by reference.

In one embodiment, the Compounds of Formula (I) are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. A Compound of Formula (I) to be orallydelivered can be in the form of tablets, capsules, gelcaps, caplets,lozenges, aqueous or oily solutions, suspensions, granules, powders,emulsions, syrups, or elixirs, for example. When a Compound of Formula(I) is incorporated into oral tablets, such tablets can be compressed,tablet triturates, enteric-coated, sugar-coated, film-coated, multiplycompressed or multiply layered. Techniques and compositions for makingsolid oral dosage forms are described in Pharmaceutical Dosage Forms:Tablets (Lieberman et al., eds., 2^(nd) ed., Marcel Dekker, Inc., 1989 &1990). Techniques and compositions for making tablets (compressed andmolded), capsules (hard and soft gelatin) and pills are also describedby King, “Tablets, Capsules, and Pills,” pp. 1553-1593 in Remington'sPharmaceutical Sciences (Osol, ed., 16^(th) ed., Mack Publishing,Easton, Pa., 1980).

Liquid oral dosage forms include aqueous and nonaqueous solutions,emulsions, suspensions, and solutions and/or suspensions reconstitutedfrom non-effervescent granules, optionally containing one or moresuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, flavoring agents, and the like.Techniques and composition for making liquid oral dosage forms aredescribed in Pharmaceutical Dosage Forms: Disperse Systems (Lieberman etal., eds., 2^(nd) ed., Marcel Dekker, Inc., 1996 & 1998).

When a Compound of Formula (I) is to be injected parenterally, it canbe, e.g., in the form of an isotonic sterile solution. Alternatively,when a Compound of Formula (I) is to be inhaled, it can be formulatedinto a dry aerosol or can be formulated into an aqueous or partiallyaqueous solution.

An orally administered Compound of Formula (I) can contain one or moreagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions can be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compositions. In these latter platforms, fluid fromthe environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time-delay material such as glycerolmonostearate or glycerol stearate can also be used. Oral compositionscan include standard excipients such as mannitol, lactose, starch,magnesium stearate, sodium saccharin, cellulose, and magnesiumcarbonate. In one embodiment, the excipients are of pharmaceuticalgrade.

In another embodiment, the Compounds of Formula (I) can be formulatedfor intravenous administration. In one embodiment, compositions forintravenous administration comprise sterile isotonic aqueous buffer.Where necessary, the compositions can also include a solubilizing agent.A Compound of Formula (I) for intravenous administration can optionallyinclude a local anesthetic such as benzocaine or prilocaine to lessenpain at the site of the injection. Generally, the ingredients aresupplied either separately or mixed together in unit dosage form, forexample, as a dry lyophilized powder or water free concentrate in ahermetically sealed container such as an ampule or sachette indicatingthe quantity of active agent. Where a Compound of Formula (I) is to beadministered by infusion, it can be dispensed, for example, with aninfusion bottle containing sterile pharmaceutical grade water or saline.Where a Compound of Formula (I) is administered by injection, an ampuleof sterile water for injection or saline can be provided so that theingredients can be mixed prior to administration.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be administered by controlled-release orsustained-release means or by delivery devices that are known to thoseof ordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548;5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide controlled- or sustained-release of one or more activeingredients using, for example, hydropropylmethyl cellulose,ethylcellulose, other polymer matrices, gels, permeable membranes,osmotic systems, multilayer coatings, microparticles, liposomes,microspheres, or a combination thereof to provide the desired releaseprofile in varying proportions. Suitable controlled- orsustained-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the disclosure. The disclosure thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled- or sustained-release.

Controlled- or sustained-release pharmaceutical compositions can have acommon goal of improving drug therapy over that achieved by theirnon-controlled or non-sustained release counterparts. In one embodiment,a controlled- or sustained-release composition comprises a minimalamount of a Compound of Formula (I) to cure or control the condition ina minimum amount of time. Advantages of controlled- or sustained-releasecompositions include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition, controlled- orsustained-release compositions can favorably affect the time of onset ofaction or other characteristics, such as blood levels of the Compound ofFormula (I), and can thus reduce the occurrence of adverse side effects.

Controlled- or sustained-release compositions can be designed toimmediately release an amount of a Compound of Formula (I), or apharmaceutically acceptable derivative thereof, that promptly producesthe desired therapeutic or prophylactic effect, and gradually andcontinually release other amounts of the Compound of Formula (I) tomaintain this level of therapeutic or prophylactic effect over anextended period of time. To maintain a constant level of the Compound ofFormula (I) in the body, the Compound of Formula (I) can be releasedfrom the dosage form at a rate that will replace the amount of Compoundof Formula (I) being metabolized and excreted from the body. Controlled-or sustained-release of an active ingredient can be stimulated byvarious conditions, including but not limited to, changes in pH, changesin temperature, concentration or availability of enzymes, concentrationor availability of water, or other physiological conditions orcompounds.

The amount of the Compound of Formula (I), or a pharmaceuticallyacceptable derivative thereof, that is effective in the treatment orprevention of a Condition can be determined by standard clinicaltechniques. In addition, in vitro or in vivo assays can optionally beemployed to help identify optimal dosage ranges. The precise dose to beemployed will also depend on the route of administration, and theseriousness of the Condition and can be decided according to thejudgment of a practitioner and/or each animal's circumstances. Suitableeffective dosage amounts, however, will, in one embodiment, range fromabout 0.01 mg/kg of body weight to about 2500 mg/kg of body weight,although they are, in another embodiment, about 100 mg/kg of body weightor less. In one embodiment, the effective dosage amount ranges fromabout 0.01 mg/kg of body weight to about 100 mg/kg of body weight of aCompound of Formula (I); in another embodiment, about 0.02 mg/kg of bodyweight to about 50 mg/kg of body weight; and in another embodiment,about 0.025 mg/kg of body weight to about 20 mg/kg of body weight.

In one embodiment, an effective dosage amount is administered aboutevery 24 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 12 h until theCondition is abated. In another embodiment, an effective dosage amountis administered about every 8 h until the Condition is abated. Inanother embodiment, an effective dosage amount is administered aboutevery 6 h until the Condition is abated. In another embodiment, aneffective dosage amount is administered about every 4 h until theCondition is abated.

The effective dosage amounts described herein refer to total amountsadministered; that is, if more than one Compound of Formula (I), or apharmaceutically acceptable derivative thereof, is administered, theeffective dosage amounts correspond to the total amount administered.

Where a cell capable of expressing TRPV1 is contacted with a Compound ofFormula (I) in vitro, the amount effective for inhibiting the TRPV1receptor function in a cell will range from about 0.01 μg/L to about 5mg/L; in one embodiment, from about 0.01 μg/L to about 2.5 mg/L; inanother embodiment, from about 0.01 μg/L to about 0.5 mg/L; and inanother embodiment, from about 0.01 μg/L to about 0.25 mg/L, of asolution or suspension of a pharmaceutically acceptable carrier orexcipient. In one embodiment, the volume of solution or suspensioncomprising the Compound of Formula (I), or a pharmaceutically acceptablederivative thereof, is from about 0.01 μL to about 1 mL. In anotherembodiment, the volume of solution or suspension is about 200 μL.

The Compounds of Formula (I), or a pharmaceutically acceptablederivative thereof, can be assayed in vitro or in vivo for the desiredtherapeutic or prophylactic activity prior to use in humans. Animalmodel systems can be used to demonstrate safety and efficacy.

The methods for treating or preventing a Condition in an animal in needthereof can further comprise administering to the animal beingadministered a Compound of Formula (I), or a pharmaceutically acceptablederivative thereof (i.e., a first therapeutic agent) a secondtherapeutic agent. In one embodiment, the second therapeutic agent isadministered in an effective amount. In one embodiment, the secondtherapeutic agent is administered in an effective amount.

The methods for inhibiting TRPV1 function in a cell capable ofexpressing TRPV1 can further comprise contacting the cell with aneffective amount of a second therapeutic agent.

An effective amount of the second therapeutic agent(s) will be known tothose skilled the art depending on the agent. However, it is well withinthe skilled artisan's purview to determine the second therapeuticagent's optimal effective-amount range. A Compound of Formula (I) andthe second therapeutic agent combined can act either additively orsynergistically to treat the same Condition, or they can actindependently of each other such that the Compound of Formula (I) treatsor prevents a first Condition and the second therapeutic agent treats orprevents a second disorder, which can be the same as the first Conditionor another disorder. In one embodiment of the disclosure, where a secondtherapeutic agent is administered to an animal for treatment of aCondition (e.g., pain), the minimal effective amount of the Compound ofFormula (I) will be less than its minimal effective amount would bewhere the second therapeutic agent is not administered. In thisembodiment, the Compound of Formula (I) and the second therapeutic agentcan act synergistically to treat or prevent a Condition. In oneembodiment, a Compound of Formula (I) is administered concurrently witha second therapeutic agent as a single composition comprising aneffective amount of a Compound of Formula (I) and an effective amount ofthe second therapeutic agent. Alternatively, a composition comprising aneffective amount of a Compound of Formula (I) and a second compositioncomprising an effective amount of the second therapeutic agent areconcurrently administered. In another embodiment, an effective amount ofa Compound of Formula (I) is administered prior or subsequent toadministration of an effective amount of the second therapeutic agent.In this embodiment, the Compound of Formula (I) is administered whilethe second therapeutic agent exerts its therapeutic effect, or thesecond therapeutic agent is administered while the Compound of Formula(I) exerts its therapeutic effect for treating or preventing aCondition.

The second therapeutic agent can be, but is not limited to, an opioidagonist, a non-opioid analgesic, a non-steroid anti-inflammatory agent,an antimigraine agent, a Cox-II inhibitor, an antiemetic, a β-adrenergicblocker, an anticonvulsant, an antidepressant, a Ca²⁺-channel blocker,an anticancer agent, an agent for treating or preventing UI, an agentfor treating or preventing an ulcer, an agent for treating or preventingIBD, an agent for treating or preventing IBS, an agent for treatingaddictive disorder, an agent for treating Parkinson's disease andparkinsonism, an agent for treating anxiety, an agent for treatingepilepsy, an agent for treating a stroke, an agent for treating aseizure, an agent for treating a pruritic condition, an agent fortreating psychosis, an agent for treating Huntington's chorea, an agentfor treating ALS, an agent for treating a cognitive disorder, an agentfor treating a migraine, an agent for treating vomiting, an agent fortreating dyskinesia, an agent for treating depression, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful opioid agonists include, but are not limited to,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene,fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine,isomethadone, ketobemidone, levorphanol, levophenacylmorphan,lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol,normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone,oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,phenazocine, phenoperidine, piminodine, piritramide, proheptazine,promedol, properidine, propiram, propoxyphene, sufentanil, tilidine,tramadol, pharmaceutically acceptable derivatives thereof, or anymixture thereof.

In certain embodiments, the opioid agonist is codeine, hydromorphone,hydrocodone, oxycodone, dihydrocodeine, dihydromorphine, morphine,tramadol, oxymorphone, pharmaceutically acceptable derivatives thereof,or any mixture thereof.

Examples of useful non-opioid analgesics include, but are not limitedto, non-steroidal anti-inflammatory agents, such as aspirin, ibuprofen,diclofenac, naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen,ketoprofen, indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen,muroprofen, trioxaprofen, suprofen, aminoprofen, tiaprofenic acid,fluprofen, bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac,tiopinac, zidometacin, acemetacin, fentiazac, clidanac, oxpinac,mefenamic acid, meclofenamic acid, flufenamic acid, niflumic acid,tolfenamic acid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam,a pharmaceutically acceptable derivative thereof, or any mixturethereof. Other suitable non-opioid analgesics include the following,non-limiting, chemical classes of analgesic, antipyretic, nonsteroidalanti-inflammatory drugs: salicylic acid derivatives, including aspirin,sodium salicylate, choline magnesium trisalicylate, salsalate,diflunisal, salicylsalicylic acid, sulfasalazine, and olsalazin;para-aminophenol derivatives including acetaminophen and phenacetin;indole and indene acetic acids, including indomethacin, sulindac, andetodolac; heteroaryl acetic acids, including tolmetin, diclofenac, andketorolac; anthranilic acids (fenamates), including mefenamic acid andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);alkanones, including nabumetone; a pharmaceutically acceptablederivative thereof; or any mixture thereof. For a more detaileddescription of the NSAIDs, see Insel, “Analgesic-Antipyretic andAnti-inflammatory Agents and Drugs Employed in the Treatment of Gout,”pp. 617-657 in Goodman & Gilman's The Pharmacological Basis ofTherapeutics (Goodman et al., Eds., 9^(th) Ed., McGraw-Hill, New York1996), and Hanson, “Analgesic, Antipyretic and Anti-Inflammatory Drugs,”pp. 1196-1221 in Remington: The Science and Practice of Pharmacy Vol 2(Gennaro, ed., 19^(th) ed., Mack Publishing, Easton, Pa., 1995), whichare hereby incorporated by reference in their entireties.

Examples of useful antimigraine agents include, but are not limited to,alpiropride, bromocriptine, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergonovine, ergot, ergotamine, flumedroxoneacetate, fonazine, ketanserin, lisuride, lomerizine, methylergonovine,methysergide, metoprolol, naratriptan, oxetorone, pizotyline,propranolol, risperidone, rizatriptan, sumatriptan, timolol, trazodone,zolmitriptan, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful Cox-II inhibitors and 5-lipoxygenase inhibitors, aswell as combinations thereof, are described in U.S. Pat. No. 6,136,839,which is hereby incorporated by reference in its entirety. Examples ofuseful Cox-II inhibitors include, but are not limited to, celecoxib,DUP-697, flosulide, meloxicam, 6-MNA, L-745337, rofecoxib, nabumetone,nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035, JTE-522,RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide, D-1367,SC-5766, PD-164387, etoricoxib, valdecoxib, parecoxib, apharmaceutically acceptable derivative thereof, or any mixture thereof.

The second therapeutic agent can also be an agent useful for reducingany potential side effects of a Compound of Formula (I). For example,the second therapeutic agent can be an antiemetic agent. Examples ofuseful antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acetylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinol, thiethylperazine,thioproperazine, tropisetron, a pharmaceutically acceptable derivativethereof, or any mixture thereof.

Examples of useful β-adrenergic blockers include, but are not limitedto, acebutolol, alprenolol, amosulabol, arotinolol, atenolol, befunolol,betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol,bufuralol, bunitrolol, bupranolol, butidrine hydrochloride, butofilolol,carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol,dilevalol, epanolol, esmolol, indenolol, labetalol, levobunolol,mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol,nebivalol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol,practolol, pronethalol, propranolol, sotalol, sulfinalol, talinolol,tertatolol, tilisolol, timolol, toliprolol, xibenolol, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful anticonvulsants include, but are not limited to,acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydantoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin,zonisamide, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful antidepressants include, but are not limited to,binedaline, caroxazone, citalopram, (S)-citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, zimeldine, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful Ca²⁺-channel blockers include, but are not limitedto, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil,prenylamine, semotiadil, terodiline, verapamil, amlodipine, aranidipine,barnidipine, benidipine, cilnidipine, efonidipine, elgodipine,felodipine, isradipine, lacidipine, lercanidipine, manidipine,nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipiie,nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine,bencyclane, etafenone, fantofarone, perhexiline, a pharmaceuticallyacceptable derivative thereof, or any mixture thereof.

Examples of useful anticancer agents include, but are not limited to,acivicin, aclarubicin, acodazole hydrochloride, acronine, adozelesin,aldesleukin, altretamine, ambomycin, ametantrone acetate,aminoglutethimide, amsacrine, anastrozole, anthramycin, asparaginase,asperlin, azacitidine, azetepa, azotomycin, batimastat, benzodepa,bicalutamide, bisantrene hydrochloride, bisnafide dimesylate, bizelesin,bleomycin sulfate, brequinar sodium, bropirimine, busulfan,cactinomycin, calusterone, caracemide, carbetimer, carboplatin,carmustine, carubicin hydrochloride, carzelesin, cedefingol,chlorambucil, cirolemycin, cisplatin, cladribine, crisnatol mesylate,cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicinhydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguaninemesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride,droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin,edatrexate, eflornithine hydrochloride, elsamitrucin, enloplatin,enpromate, epipropidine, epirubicin hydrochloride, erbulozole,esorubicin hydrochloride, estramustine, estramustine phosphate sodium,etanidazole, etoposide, etoposide phosphate, etoprine, fadrozolehydrochloride, fazarabine, fenretinide, floxuridine, fludarabinephosphate, fluorouracil, flurocitabine, fosquidone, fostriecin sodium,gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicinhydrochloride, ifosfamide, ilmofosine, interleukin II (includingrecombinant interleukin II or rIL2), interferon alpha-2a, interferonalpha-2b, interferon alpha-n1, interferon alpha-n3, interferon beta-I a,interferon gamma-I b, iproplatin, irinotecan hydrochloride, lanreotideacetate, letrozole, leuprolide acetate, liarozole hydrochloride,lometrexol sodium, lomustine, losoxantrone hydrochloride, masoprocol,maytansine, mechlorethamine hydrochloride, megestrol acetate,melengestrol acetate, melphalan, menogaril, mercaptopurine,methotrexate, methotrexate sodium, metoprine, meturedepa, mitindomide,mitocarcin, mitocromin, mitogillin, mitomalcin, mitomycin, mitosper,mitotane, mitoxantrone hydrochloride, mycophenolic acid, nocodazole,nogalamycin, ormaplatin, oxisuran, paclitaxel, pegaspargase, peliomycin,pentamustine, peplomycin sulfate, perfosfamide, pipobroman, piposulfan,piroxantrone hydrochloride, plicamycin, plomestane, porfimer sodium,porfiromycin, prednimustine, procarbazine hydrochloride, puromycin,puromycin hydrochloride, pyrazofurin, riboprine, rogletimide, safingol,safingol hydrochloride, semustine, simtrazene, sparfosate sodium,sparsomycin, spirogermanium hydrochloride, spiromustine, spiroplatin,streptonigrin, streptozocin, sulofenur, talisomycin, tecogalan sodium,tegafur, teloxantrone hydrochloride, temoporfmin, teniposide,teroxirone, testolactone, thiamiprine, thioguanine, thiotepa,tiazofurin, tirapazamine, toremifene citrate, trestolone acetate,triciribine phosphate, trimetrexate, trimetrexate glucuronate,triptorelin, tubulozole hydrochloride, uracil mustard, uredepa,vapreotide, verteporfin, vinblastine sulfate, vincristine sulfate,vindesine, vindesine sulfate, vinepidine sulfate, vinglycinate sulfate,vinleurosine sulfate, vinorelbine tartrate, vinrosidine sulfate,vinzolidine sulfate, vorozole, zeniplatin, zinostatin, zorubicinhydrochloride, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of other anticancer drugs include, but are not limited to,20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanthraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; 9-dihydrotaxol; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-1 receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor l-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; zinostatinstimalamer, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing UIinclude, but are not limited to, propantheline, imipramine, hyoscyamine,oxybutynin, dicyclomine, a pharmaceutically acceptable derivativethereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing anulcer include, antacids such as aluminum hydroxide, magnesium hydroxide,sodium bicarbonate, and calcium bicarbonate; sucraflate; bismuthcompounds such as bismuth subsalicylate and bismuth subcitrate; H₂antagonists such as cimetidine, ranitidine, famotidine, and nizatidine;H⁺, K⁺-ATPase inhibitors such as omeprazole, iansoprazole, andlansoprazole; carbenoxolone; misprostol; antibiotics such astetracycline, metronidazole, timidazole, clarithromycin, andamoxicillin; a pharmaceutically acceptable derivative thereof; or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing IBDinclude, but are not limited to, anticholinergic drugs; diphenoxylate;loperamide; deodorized opium tincture; codeine; broad-spectrumantibiotics such as metronidazole; sulfasalazine; olsalazie; mesalamine;prednisone; azathioprine; mercaptopurine; methotrexate; apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing IBSinclude, but are not limited to, propantheline; muscarine receptorantogonists such as pirenzapine, methoctramine, ipratropium, tiotropium,scopolamine, methscopolamine, homatropine, homatropine methylbromide,and methantheline; antidiarrheal drugs such as diphenoxylate andloperamide; a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing anaddictive disorder include, but are not limited to, methadone,desipramine, amantadine, fluoxetine, buprenorphine, an opiate agonist,3-phenoxypyridine, levomethadyl acetate hydrochloride, serotoninantagonists, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventingParkinson's disease and parkinsonism include, but are not limited to,carbidopa/levodopa, pergolide, bromocriptine, ropinirole, pramipexole,entacapone, tolcapone, selegiline, amantadine, trihexyphenidylhydrochloride, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing anxietyinclude, but are not limited to, benzodiazepines, such as alprazolam,brotizolam, chlordiazepoxide, clobazam, clonazepam, clorazepate,demoxepam, diazepam, estazolam, flumazenil, flurazepam, halazepam,lorazepam, midazolam, nitrazepam, nordazepam, oxazepam, prazepam,quazepam, tanazepam, and triazolam; non-benzodiazepine agents, such asbuspirone, gepirone, ipsapirone, tiospirone, zolpicone, zolpidem, andzaleplon; tranquilizers, such as barbituates, e.g., amobarbital,aprobarbital, butabarbital, butalbital, mephobarbital, methohexital,pentobarbital, phenobarbital, secobarbital, and thiopental; propanediolcarbamates, such as meprobamate and tybamate; a pharmaceuticallyacceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingepilepsy include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, benzodiazepines, γ vinyl GABA, acetazolamide,felbamate, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing strokeinclude, but are not limited to, anticoagulants such as heparin, agentsthat break up clots such as streptokinase or tissue plasminogenactivator, agents that reduce swelling such as mannitol orcorticosteroids, acetylsalicylic acid, a pharmaceutically acceptablederivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing aseizure include, but are not limited to, carbamazepine, ethosuximide,gabapentin, lamotrignine, phenobarbital, phenytoin, primidone, valproicacid, trimethadione, bemzodiaepines, gabapentin, lamotrigine, γ-vinylGABA, acetazolamide, felbamate, a pharmaceutically acceptable derivativethereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing apruritic condition include, but are not limited to, naltrexone;nalmefene; danazol; tricyclics such as amitriptyline, imipramine, anddoxepin; antidepressants such as those given below, menthol; camphor;phenol; pramoxine; capsaicin; tar; steroids; antihistamines; apharmaceutically acceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingpsychosis include, but are not limited to, phenothiazines such aschlorpromazine hydrochloride, mesoridazine besylate, and thoridazinehydrochloride; thioxanthenes such as chloroprothixene and thiothixenehydrochloride; clozapine; risperidone; olanzapine; quetiapine;quetiapine fumarate; haloperidol; haloperidol decanoate; loxapinesuccinate; molindone hydrochloride; pimozide; ziprasidone; apharmaceutically acceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingHuntington's chorea include, but are not limited to, haloperidol,pimozide, a pharmaceutically acceptable derivative thereof, or anymixture thereof.

Examples of useful therapeutic agents for treating or preventing ALSinclude, but are not limited to, baclofen, neurotrophic factors,riluzole, tizanidine, benzodiazepines such as clonazepan, dantrolene, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingcognitive disorders include, but are not limited to, agents for treatingor preventing dementia such as tacrine; donepezil; ibuprofen;antipsychotic drugs such as thioridazine and haloperidol; antidepressantdrugs such as those given above; a pharmaceutically acceptablederivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventing amigraine include, but are not limited to, alpiropride, bromocriptine,dihydroergotamine, dolasetron, ergocornine, ergocorninine, ergocryptine,ergonovine, ergot, ergotamine, flumedroxone acetate, fonazine,ketanserin, lisuride, lomerizine, methylergonovine, methysergide,metoprolol, naratriptan, oxetorone, pizotyline, propranolol,risperidone, rizatriptan, sumatriptan, timolol, trazodone, zolmitriptan,a pharmaceutically acceptable derivative thereof, or any mixturethereof.

Examples of useful therapeutic agents for treating or preventingvomiting include, but are not limited to, 5-HT₃ receptor antagonistssuch as ondansetron, dolasetron, granisetron, and tropisetron; dopaminereceptor antagonists such as prochlorperazine, thiethylperazine,chlorpromazin, metoclopramide, and domperidone; glucocorticoids such asdexamethasone; benzodiazepines such as lorazepam and alprazolam; apharmaceutically acceptable derivative thereof; or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdyskinesia include, but are not limited to, reserpine, tetrabenazine, apharmaceutically acceptable derivative thereof, or any mixture thereof.

Examples of useful therapeutic agents for treating or preventingdepression include, but are not limited to, tricyclic antidepressantssuch as amitryptyline, amoxapine, bupropion, clomipramine, desipramine,doxepin, imipramine, maprotilinr, nefazadone, nortriptyline,protriptyline, trazodone, trimipramine, and venlaflaxine; selectiveserotonin reuptake inhibitors such as citalopram, (S)-citalopram,fluoxetine, fluvoxamine, paroxetine, and setraline; monoamine oxidaseinhibitors such as isocarboxazid, pargyline, phenelzine, andtranylcypromine; psychostimulants such as dextroamphetamine andmethylphenidate; a pharmaceutically acceptable derivative thereof; orany mixture thereof.

A Compound of Formula (I), or a pharmaceutically acceptable derivativethereof, and the second therapeutic agent can act additively or, in oneembodiment, synergistically. In one embodiment, a Compound of Formula(I) is administered concurrently with a second therapeutic agent; forexample, a composition comprising an effective amount of a Compound ofFormula (I) and an effective amount of a second therapeutic agent can beadministered. Alternatively, a composition comprising an effectiveamount of a Compound of Formula (I) and a different compositioncomprising an effective amount of a second therapeutic agent can beconcurrently administered. In another embodiment, an effective amount ofa Compound of Formula (I) is administered prior or subsequent toadministration of an effective amount of a second therapeutic agent. Inthis embodiment, the Compound of Formula (I) is administered while thesecond therapeutic agent exerts its therapeutic effect, or the secondtherapeutic agent is administered while the Compound of Formula (I)exerts its therapeutic effect for treating or preventing a Condition.

A composition of the disclosure is prepared by a method comprisingadmixing a Compound of Formula (I) or a pharmaceutically acceptablederivative thereof with a pharmaceutically acceptable carrier orexcipient. Admixing can be accomplished using methods known for admixinga compound (or derivative) and a pharmaceutically acceptable carrier orexcipient. In one embodiment, the Compound of Formula (I) is present inthe composition in an effective amount.

4.7 Kits

The disclosure further provides kits that can simplify the handling andadministration of a Compound of Formula (I) to an animal.

In one embodiment, a kit of the disclosure comprises a unit dosage formof a Compound of Formula (I). In one embodiment, the unit dosage formcomprises a first container, which can be sterile, containing aneffective amount of a Compound of Formula (I) and a pharmaceuticallyacceptable carrier or excipient. The kit can further comprise a label orprinted instructions instructing the use of the Compound of Formula (I)to treat or prevent a Condition. The kit can further comprise a unitdosage form of a second therapeutic agent, for example, a secondcontainer containing an effective amount of the second therapeutic agentand a pharmaceutically acceptable carrier or excipient. In anotherembodiment, the kit comprises a container containing an effective amountof a Compound of Formula (I), an effective amount of a secondtherapeutic agent and a pharmaceutically acceptable vehicle, carrier, orexcipient. Examples of second therapeutic agents include, but are notlimited to, those listed above.

Kits of the disclosure can further comprise a device that is useful foradministering the unit dosage forms. Examples of such a device include,but are not limited to, a syringe, a drip bag, a patch, an inhaler, andan enema bag.

The following examples are set forth to assist in understanding theinvention and should not be construed as specifically limiting theinvention described and claimed herein. Such variations of theinvention, including the substitution of all equivalents now known orlater developed, that would be within the purview of those skilled inthe art, and changes in formulation or changes in experimental design,are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

Certain Examples below relate to the synthesis of illustrative Compoundsof Formulae (I) and/or (II).

5.1 Example 1 Preparation of Compound C126(r)

Tert-butyl 4-(5-bromo-3-fluoropyridin-2-yl)-piperazine-1-carboxylate(103)

A reaction mixture of 5-bromo-2-chloro-3-fluoropyridine (101, 8.0 g,38.02 mmol, Oakwood Products, Inc., West Columbia, S.C.) and tert-butylpiperazine-1-carboxylate (102, 7.08 g, 38.02 mmol, Sigma-Aldrich) inDMSO (32 mL) was heated at 100° C. for 16 h. The mixture was cooled to atemperature of about 25° C., poured onto cold 10% aqueous sodiumcarbonate, and extracted with EtOAc. The organic layer was washed withwater, washed with brine, dried over sodium sulfate, and concentrated toprovide 15.5 g of a semi-solid. The semi-solid was washed with hexanesand filtered. The filtrate was concentrated to provide 7.5 g of aresidue. The residue was chromatographed on a silica gel column elutedwith a gradient of from 100% hexanes to 10:90 EtOAc:hexanes to provide103 as a solid (24% yield).

(E)-tert-butyl4-(3-fluoro-5-(prop-1-enyl)pyridin-2-yl)piperazine-1-carboxylate (105)

Under an argon atmosphere, to a solution of 103 (3.30 g, 9.16 mmol) and(E)-prop-1-enylboronic acid (104, 0.95 g, 11.0 mmol, Sigma-Aldrich) wasadded a 1M solution of tetra(n-butyl)ammonium fluoride (TBAF) in THF (22mL, 22.0 mmol, Sigma-Aldrich) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(Pd(DPPF)Cl₂, 0.075 g, 0.092 mmol, Sigma-Aldrich). The resultingreaction mixture was stirred at reflux for 2 hours, cooled to atemperature of about 25° C., diluted with water, and extracted withEtOAc. The organic layer was washed with brine and concentrated toprovide 3.6 g of a residue. The residue was chromatographed on a silicagel column eluted with EtOAc:hexanes to provide 105 (91% yield).

Tert-butyl4-(5-((1S,2S)-1,2-dihydroxypropyl)-3-fluoropyridin-2-yl)piperazine-1-carboxylate(106)

To a solution of 105 (2.67 g, 8.29 mmol) in tert-butanol (80 mL) andwater (80 mL) was added methanesulfonamide (0.79 g, 8.29 mmol,Sigma-Aldrich). The mixture was cooled to 5° C. and AD-mix-α (11.50 g,8.29 mmol) was added to form a reaction mixture. After warming thereaction mixture to a temperature of about 25° C. and stirring for 16hours, excess solid sodium sulfite was added and the resulting slurrywas allowed to stir at 15° C. for 30 min. The mixture was extractedtwice with EtOAc. The organic portions were combined, washed with brine,dried (Na₂SO₄), and concentrated under reduced pressure. The residue waschromatographed on a silica gel column eluted with 50:50 EtOAc:hexanesand 70:30 EtOAc:hexanes to provide 106 as a solid (>99% yield).

(1S,2S)-1-(5-fluoro-6-(piperazin-1-yl)pyridin-3-yl)propane-1,2-diol(107)

To a solution of 106 (3.0 g, 8.65 mmol) in DCM (25 mL) was added 4N HClin dioxane (2.51 mL, 43.2 mmol). The resulting reaction mixture wasstirred at a temperature of about 25° C. in a closed vessel for 16 h; asuspension formed. The suspension was stirred with diethyl ether; asolid precipitated. The precipitate was collected by filtration andwashed several times with ether to provide 107 (91% yield) as a tansolid which, being >99% pure as analyzed by LC/MS, was used directly inthe next step.

4-[5-((1S,2S)-1,2-Dihydroxy-propyl)-3-fluoro-pyridin-2-yl]piperazine-1-carboxylicacid (6-methyl-benzothiazol-2-yl)-amide (Compound C126(r))

A suspension of 107 (200 mg, 0.61 mmol) andN-(6-methylbenzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (108, 160mg, 0.61 mmol) in DCM (6.0 mL) was cooled in an ice bath.Diisopropylethylamine (DIEA, 2.0 mL, Sigma-Aldrich) was added to form areaction mixture. The reaction mixture was stirred at a temperature ofabout 25° C. for 16 hours; a precipitate formed. The precipitate wasfiltered and washed with DCM. Thereafter, the precipitate was dissolvedin 20:80 MeOH:DCM, concentrated on silica, and chromatographed on asilica gel column eluted with a gradient of from 30:70 EtOAc:DCM to80:20 EtOAc:DCM to provide C126(r) as a white solid (24% yield). ¹H NMR(DMSO-d₆) δ: 0.88 (3H, d, J=6.4 Hz), 2.37 (3H, s), 3.38 (4H, m), 3.69(5H, m), 4.37 (1H, t, J=4.8 Hz), 4.65 (1H, d, J=4.6 Hz), 5.28 (1H, d,J=4.4 Hz), 7.18 (1H, m), 7.44 (1H, d, J=14.3 Hz), 7.52 (1H, br s), 7.66(1H, br s), 7.97 (1H, s), 11.20 (1H, br s). LC/MS (M+1): m/z=446.

Compound 108 was prepared as follows:

To a solution of 6-methylbenzo[d]thiazol-2-amine (109, 328 mg, 2 mmol,Sigma-Aldrich) in DMF (5 mL) was added di(1H-imidazol-1-yl)methanone(110, 357 mg, 2.2 mmol, Sigma-Aldrich) at 0° C. Under vigorous stirring,the resulting reaction mixture was slowly allowed to warm to atemperature of about 25° C. over 14 h. A white precipitate formed. Theprecipitate was collected by filtration under reduced pressure, washedtwice with EtOAc (10 mL for each wash), and dried under reduced pressureto provide 108 (yield >99%).

5.2 Example 2 Preparation of Compounds B122(j), B122(k), B122(o),B122(p), B125(j), B125(k), B125(o), B125(p), B155(h), B155(j), B155(o),B158(j), B158(o), C4(r), C123(r), C125(r), and C170(r)

Using procedures similar to those described in Example 1 above, thefollowing Compounds of Formula (I) were prepared.

B122(j):(R)-N-(benzo[d]thiazol-2-yl)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.1 Hz), 1.07 (3H, d, J=6.4 Hz),3.08-3.45 (3H, m), 3.75-3.54 (2H, m), 3.94-4.30 (3H, m), 4.35 (1H, t,J=5.0 Hz), 4.66 (1H, d, J=4.6 Hz), 5.28 (1H, d, J=4.4 Hz), 7.20 (1H, t,J=7.4 Hz), 7.70-7.28 (3H, m), 7.72-7.91 (1H, m), 7.96 (1H, s), 11.33(1H, br s). LC/MS (M+1): m/z=447.

B122(k):(S)-N-(benzo[d]thiazol-2-yl)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.4 Hz), 1.07 (3H, d, J=6.6 Hz),3.28-3.39 (3H, m), 3.60-3.70 (2H, m), 4.20-4.22 (3H, m), 4.34 (1H, d,J=5.5 Hz), 4.67 (1H, br s), 5.25 (1H, br s), 7.20 (1H, t, J=7.5 Hz),7.32-7.51 (3H, m), 7.80 (1H, br s), 7.96 (1H, s), 11.32 (1H, br s).LC/MS (M+1): m/z=447.

B122(o):(R)-N-(benzo[d]thiazol-2-yl)-4-{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.88 (3H, d, J=6.3 Hz), 1.05 (3H, d, J=6.4 Hz),2.99-3.46 (3H, m), 3.50-3.60 (1H, m), 3.61-3.75 (1H, m), 4.00-4.31 (3H,m), 4.33 (1H, d, J=5.3 Hz), 4.66 (1H, br s), 5.27 (1H, br s), 6.89 (1H,t, J=7.4 Hz), 7.11 (1H, t, J=7.1 Hz), 7.25 (1H, d, J=7.9 Hz), 7.39 (1H,dd, J=1.8, 14.5 Hz), 7.54 (1H, d, J=7.2 Hz), 7.95 (1H, s). LC/MS (M+1):m/z=447.

B122(p):(S)-N-(benzo[d]thiazol-2-yl)-4-{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.6 Hz),3.21-3.35 (3H, m), 3.62-3.66 (2H, m), 4.03-4.36 (4H, m), 4.66 (1H, d,J=4.0 Hz), 5.28 (1H, d, J=4.0 Hz), 7.20 (1H, t, J=7.5 Hz), 7.33-7.50(3H, m), 7.80 (1H, br s), 7.95 (1H, s), 11.27 (1H, br s). LC/MS (M+1):m/z=447.

B125(j):(R)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(6-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.6 Hz),3.10-3.46 (3H, m), 3.55-3.75 (2H, m), 4.03 (1H, d, J=13.9 Hz), 4.11-4.28(2H, m), 4.35 (1H, t, J=4.7 Hz), 4.66 (1H, d, J=4.6 Hz), 5.28 (1H, d,J=4.4 Hz), 7.20 (1H, td, J=2.7, 9.1 Hz), 7.41 (1H, dd, J=1.6, 14.4 Hz),7.50-7.59 (1H, m), 7.77 (1H, dd, J=2.6, 8.5 Hz), 7.95 (1H, s), 11.43(1H, br s). LC/MS (M+1): m/z=465.

B125(k):(S)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.4 Hz),3.24-3.40 (3H, m), 3.71-3.60 (2H, m), 4.04-4.20 (3H, m), 4.35 (1H, t,J=4.6 Hz), 4.65 (1H, d, J=4.6 Hz), 5.27 (1H, d, J=4.6 Hz), 7.24-7.38(3H, m), 7.82 (1H, br s), 7.96 (1H, s), 11.27 (1H, br s). LC/MS (M+1):m/z=465.

B125(o):(R)-4-{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(6-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.4 Hz), 1.07 (3H, d, J=6.6 Hz),3.43-3.08 (3H, m), 3.55-3.74 (2H, m), 3.97-4.08 (1H, m), 4.13-4.26 (2H,m), 4.34 (1H, d, J=5.0 Hz), 4.66 (1H, br s), 5.28 (1H, br s), 7.15 (1H,td, J=2.7, 9.1 Hz), 7.41 (1H, dd, J=1.6, 14.4 Hz), 7.48 (1H, dd, J=4.7,8.7 Hz), 7.70 (1H, dd, J=2.6, 8.7 Hz), 7.95 (1H, s). LC/MS (M+1):m/z=465.

B125(p): (S)-4-Z{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.6 Hz),3.21-3.35 (3H, m), 3.62-3.69 (2H, m), 4.02-4.20 (3H, m), 4.34 (1H, t,J=4.6 Hz), 4.66 (1H, d, J=4.6 Hz), 5.28 (1H, d, J=4.6 Hz), 7.21 (1H, dt,J=1.7, 9.0 Hz), 7.41 (1H, dd, J=1.7, 14.3 Hz), 7.55 (1H, br s), 7.77(1H, d, J=9.0 Hz), 7.95 (1H, s), 11.30 (1H, br s). LC/MS (M+1): m/z=465.

B155(h): (S)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (CDCl₃) δ: 1.16 (3H, d, J=6.3 Hz), 1.31 (3H, d, J=6.7 Hz),2.97-2.92 (1H, m), 3.11-3.16 (2H, m), 3.39 (1H, dt, J=3.5, 12.6 Hz),3.89-4.01 (4H, m), 4.40-4.42 (3H, m), 6.99 (1H, dt, J=2.4, 8.8 Hz),7.30-7.34 (2H, m), 7.65 (1H, dd, J=5.2, 8.5 Hz), 7.98 (1H, s), 9.31 (1H,br s). LC/MS (M+1): m/z=465.

B155(j):(R)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.4 Hz),3.10-3.44 (3H, m), 3.76-3.52 (2H, m), 4.04 (1H, d, J=13.9 Hz), 4.13-4.26(2H, m), 4.29-4.38 (1H, m), 4.61-4.69 (1H, m), 5.28 (1H, d, J=4.3 Hz),7.02 (1H, td, J=9.1, 2.4 Hz), 7.25-7.35 (1H, m), 7.41 (1H, dd, J=14.3,1.5 Hz), 7.81 (1H, dd, J=5.5, 8.7 Hz), 7.95 (1H, s), 11.60 (1H, br s).LC/MS (M+1): m/z=465.

B155(o):(R)-4-{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.07 (3H, d, J=6.6 Hz),3.08-3.47 (3H, m), 3.56-3.74 (2H, m), 4.04 (1H, d, J=12.7 Hz), 4.27-4.13(2H, m), 4.34 (1H, d, J=5.0 Hz), 4.66 (1H, br s), 5.27 (1H, br s), 6.98(1H, td, J=2.2, 9.0 Hz), 7.26 (1H, dd, J=2.1, 10.1 Hz), 7.41 (1H, dd,J=1.3, 14.4 Hz), 7.77 (1H, dd, J=5.6, 8.5 Hz), 7.95 (1H, s). LC/MS(M+1): m/z=465.

B158(j):(R)-N-(5,6-difluorobenzo[d]thiazol-2-yl)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.06 (3H, d, J=6.4 Hz),3.04-3.42 (4H, m), 3.51-3.76 (2H, m), 3.97-4.10 (1H, m), 4.11-4.25 (1H,m), 4.30-4.38 (1H, m), 4.65 (1H, d, J=4.3 Hz), 5.27 (1H, d, J=4.6 Hz),7.35-7.51 (2H, m), 7.80-7.98 (2H, m), 11.52 (1H, br s). LC/MS (M+1):m/z=483.

B158(o):(R)-N-(5,6-difluorobenzo[d]thiazol-2-yl)-4-{5-[(1R,2R)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.87 (3H, d, J=6.3 Hz), 1.06 (3H, d, J=6.6 Hz),3.06-3.44 (3H, m), 3.52-3.74 (2H, m), 3.94-4.08 (1H, m), 4.10-4.26 (2H,m), 4.29-4.40 (1H, m), 4.58-4.72 (1H, m), 5.19-5.34 (1H, m), 7.34-7.52(2H, m), 7.81-7.99 (2H, m), 11.49 (1H, br s). LC/MS (M+1): m/z=483.

C4(r):4-{3-Chloro-5-[(1S,2S)-1,2-dihydroxypropyl]pyridin-2-yl}-N-(6-fluorobenzo[d]thiazol-2-yl)piperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.89 (3H, d, J=6.2 Hz), 3.24-3.31 (4H, m), 3.69-3.73(5H, m), 4.40 (1H, d, J=4.4 Hz), 4.67 (1H, br s), 5.34 (1H, br s), 7.14(1H, dt, J=8.6, 1.7 Hz), 7.47 (1H, dd, J=8.6, 4.6 Hz), 7.67-7.71 (2H,m), 8.15 (1H, d, J=1.7 Hz), 11.52 (1H, br s). LC/MS (M+1): m/z=466.

C123(r):N-(6-chlorobenzo[d]thiazol-2-yl)-4-(5-((1S,2S)-1,2-dihydroxypropyl)-3-fluoropyridin-2-yl)piperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.88 (3H, d, J=6.4 Hz), 3.40 (4H, m), 3.70 (5H, m),4.37 (1H, t, J=4.8 Hz), 4.65 (1H, d, J=6.8 Hz), 5.28 (1H, d, J=4.7 Hz),7.39 (1H, d, J=7.5 Hz), 7.44 (1H, d, J=14.3 Hz), 7.63 (1H, br s), 7.97(1H, s), 8.03 (1H, br s), 11.40 (1H, br s). LC/MS (M+1): m/z=466.

C125(r):4-(5-((1S,2S)-1,2-dihydroxypropyl)-3-fluoropyridin-2-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)piperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.88 (3H, d, J=6.4 Hz), 3.39 (4H, m), 3.69 (5H, m),4.37 (1H, t, J=4.82 Hz), 4.66 (1H, d, J=4.6 Hz), 5.28 (1H, d, J=4.6 Hz),7.22 (1H, t, J=9.4 Hz), 7.44 (1H, d, J=14.2 Hz), 7.64 (1H, br s), 7.81(1H, br s), 7.97 (1H, s), 11.33 (1H, br s). LC/MS (M+1): m/z=450.

C170(r):4-(5-((1S,2S)-1,2-dihydroxypropyl)-3-fluoropyridin-2-yl)-N-(5,6-dimethylbenzo[d]thiazol-2-yl)piperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.88 (3H, d, J=6.4 Hz), 2.28 (6H, d, J=5.7 Hz), 3.38(4H, m), 3.70 (5H, m), 4.36 (1H, d, J=5.5 Hz), 4.66 (1H, br s), 5.28(1H, br s), 7.44 (1H, d, J=12.7 Hz), 7.46 (1H, br s), 7.56 (1H, br s),7.97 (1H, s), 11.17 (1H, br s). LC/MS (M+1): m/z=460.

5.3 Example 3 Preparation of Compound BB

Using procedures similar to those described in Example 1 above, theCompound BB was prepared.

BB:(S)-4-{5-[(1S,2S)-1,2-dihydroxypropyl]-3-fluoropyridin-2-yl}-N-(6-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 0.86 (3H, d, J=6.1 Hz), 1.24 (3H, d, J=6.6 Hz), 2.85(1H, t, J=11.6 Hz), 3.05 (1H, d, J=11.6 Hz), 3.24-3.33 (1H, m),3.65-3.73 (1H, m), 3.77 (1H, d, J=12.9 Hz), 3.93 (1H, d, J=12.3 Hz),4.16 (1H, br s), 4.36 (1H, t, J=4.6 Hz), 4.57 (1H, br s), 4.66 (1H, d,J=4.8 Hz), 5.29 (1H, d, J=4.6 Hz), 7.21 (1H, t, J=8.8 Hz), 7.43 (1H, d,J=14.3 Hz), 7.64 (1H, br s), 7.79 (1H, br s), 7.95 (1H, s), 11.30 (1H,br s). LC/MS (M+1): m/z=464.

5.4 Example 4 Preparation of Compound A155(a)

2-Chloro-3-fluoro-5-vinylpyridine (112)

To a solution of 101 (5.00 g, 23.8 mmol) and4,4,6-trimethyl-2-vinyl-1,3,2-dioxaborinane (111, 3.29 g, 21.39 mmol,Sigma-Aldrich) in a mixture of TBAF (30.0 mL) and THF (64.0 mL) under anargon atmosphere was added bis(triphenylphosphine)dichloropalladium(II)catalyst (Pd(PPh₃)₂Cl₂, 1.33 g, 1.90 mmol, Sigma-Aldrich) and K₂CO₃(8.20 g, 59.4 mmol). The resulting reaction mixture was heated to 60° C.and held for 16 hrs in a sealed bottle. The mixture was cooled to atemperature of about 25° C., diluted with water, and extracted withEtOAc. The organic layer was separated, washed with brine, andconcentrated. The residue was chromatographed on a silica gel columneluted with EtOAc:hexanes to provide 3.2 g of 112 as a colorless oil(85% yield). ¹H NMR (CDCl₃) δ: 5.48 (1H, d, J=10.97 Hz), 5.83 (1H, d,J=17.62 Hz), 6.68 (1H, dd, J=10.97, 17.62 Hz), 7.52 (1H, d, J=1.60 Hz),8.20 (1H, d, J=1.60 Hz). LC/MS (M+1): m/z=158.

(S)-1-(6-Chloro-5-fluoropyridin-3-yl)ethane-1,2-diol (113)

To a solution of 112 (5.00 g, 31.75 mmol) in water (162 mL) andtert-butanol (162 mL) cooled to 0° C. with an ice bath was added AD-mixα (54.6 g, Sigma-Aldrich) to form a reaction mixture. With the bath iceleft in place, the reaction mixture was allowed to warm to a temperatureof about 25° C. After 16 hrs, excess solid sodium sulfite (60 g) wasadded and the resulting slurry was allowed to stir at a temperature ofabout 25° C. for 30 min. The mixture was extracted twice with EtOAc. Theorganic portions were combined, washed with brine, dried (Na₂SO₄), andconcentrated under reduced pressure. The resulting mixture waschromatographed on a silica gel column eluted with a gradient of from50:50 EtOAc:hexanes to 100% EtOAc to provide 5.39 g of 113 as a whitesolid (89% yield). ¹H NMR (CDCl₃) δ: 2.16 (1H, t, J=5.60 Hz), 2.88 (1H,d, J=3.54 Hz), 3.66 (1H, m), 3.84 (1H, m), 4.91 (1H, m), 7.59 (1H, dd,J=1.61, 8.73 Hz), 8.29 (1H, d, J=1.88 Hz). LC/MS (M+1): m/z=192.

(S)-2-Chloro-5-(2,2-dimethyl-1,3-dioxolan-4-yl)-3-fluoropyridine (114)

A suspension of 113 (5.39 g, 28.2 mmol) in 2,2-dimethoxypropane (58 mL,Sigma-Aldrich) was cooled with an ice bath. Para-toluene sulfonic acidmonohydrate (PTSA, 0.54 g, 2.82 mmol, Sigma-Aldrich) was added to form areaction mixture. The ice bath was removed and the reaction mixture wasstirred at a temperature of about 25° C. for 16 hrs. Thereafter, themixture was cooled with an ice bath, treated with saturated aqueoussodium bicarbonate, and extracted with EtOAc. The organic layer wasseparated, washed with brine, dried (Na₂SO₄), and concentrated toprovide 5.65 g of 114 as an oil (87% yield). ¹H NMR (CDCl₃) δ: 1.48 (3H,s), 1.54 (3H, s), 3.71 (1H, m), 4.37 (1H, m), 5.11 (1H, t, J=6.76 Hz),7.53 (1H, dd, J=1.93, 8.63 Hz), 8.18 (1H, d, J=1.88 Hz). LC/MS (M+1):m/z=232.

(S)-Tert-butyl-4-{5-[(S)-2,2-dimethyl-1,3-dioxolan-4-yl]-3-fluoropyridin-2-yl}-2-methylpiperazine-1-carboxylate(116)

To a solution of 114 (1.60 g, 6.91 mmol) in toluene (21.1 mL) under anargon atmosphere was added (S)-tert-butyl2-methylpiperazine-1-carboxylate (115, 1.38 g, 6.91 mmol, AK Scientific,Inc., Union City, Calif.), sodium tert-butoxide (0.73 g, 7.60 mmol,Sigma-Aldrich), and2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (i.e., “X-Phos,”0.49 g, 1.04 mmol, Sigma-Aldrich). The mixture was degassed under argonand then tris(dibenzylideneacetone) dipalladium (Pd₂(DBA)₃, 0.63 g, 0.69mmol, Sigma-Aldrich) was added to form a reaction mixture. The reactionmixture, heated in an oil bath maintained at temperature within therange of from 80° C. to 85° C., was stirred for 1.5 hours. Thereafter,the mixture was cooled to a temperature of about 25° C., poured ontocold water, and extracted with EtOAc. The organic layer was separated,washed with brine, and concentrated to an oil which was chromatographedon a silica gel column eluted with 10:90 EtOAc:hexanes and 20:80EtOAc:hexanes to provide 1.71 g of 116 as a solid (63% yield). ¹H NMR(CDCl₃) δ: 1.25 (3H, d, J=6.80 Hz), 1.46 (3H, s), 1.48 (9H, s), 1.53(3H, s), 2.89 (1H, dt, J=3.29, 13.59 Hz), 3.09 (1H, dd, J=3.73, 12.06Hz), 3.23 (1H, dt, J=2.85, 13.59 Hz), 3.69 (1H, t, J=7.89 Hz), 3.83 (1H,d, J=12.72 Hz), 3.92 (1H, d, J=13.81 Hz), 4.01 (1H, d, J=12.90 Hz), 4.27(1H, t, J=6.14 Hz), 4.31 (1H, brs), 5.01 (1H, t, J=7.24 Hz), 7.30 (1H,d, J=1.97 Hz), 7.95 (1H, s). LC/MS (M+1): m/z=396.

(S)-1-{5-Fluoro-6-[(S)-3-methylpiperazin-1-yl]pyridin-3-yl}ethane-1,2-diol(117)

To a solution of 116 (1.71 g, 4.33 mmol) in DCM (9.60 mL) and MeOH (1.50mL) was added 4N HCl in dioxane (6.49 mL) to form a reaction mixture.The reaction mixture was stirred at a temperature of about 25° C. in aclosed vessel for 16 h. Thereafter, the resulting suspension was stirredwith diethyl ether. The solid precipitate was collected on filter paperand washed several times with diethyl ether to provide 1.25 g of 117 asa tan solid (88% yield) which, being >99% pure as analyzed by LC/MS, wasused directly in the next step.

(S)-4-{5-[(S)-1,2-Dihydroxyethyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide(Compound A155(a))

A suspension of 117 (0.18 g, 0.40 mmol) andN-(5-fluorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide (118, 0.105g, 0.40 mmol) in DCM (5 mL) was cooled with an ice bath. DIEA (1.0 mL)was added to form a reaction mixture. The reaction mixture was stirredat a temperature of about 25° C. for about 16 h. The mixture was dilutedwith DCM (100 mL), washed with saturated aqueous NaHCO₃, washed twicewith brine, dried, and concentrated. The obtained residue waschromatographed on a silica gel column eluted with a gradient of from100% DCM to 10:90 MeOH:DCM to provide 0.095 g of Compound A155(a) as awhite foam (53% yield). ¹H NMR (DMSO-d⁶) δ: 1.24 (3H, d, J=6.80 Hz),2.86 (1H, dt, J=3.51, 12.50 Hz), 3.05 (1H, dd, J=3.29, 12.24 Hz), 3.30(1H, t, J=12.28 Hz), 3.41 (1H, m, J=6.14 Hz), 3.48 (1H, m, J=5.26 Hz),3.77 (1H, d, J=12.94 Hz), 3.93 (1H, d, J=11.62 Hz), 4.19 (1H, d, J=12.28Hz), 4.52 (1H, qt, J=5.48 Hz), 4.61 (1H, brs), 4.77 (1H, t, J=6.14 Hz),5.36 (1H, d, J=4.60 Hz), 7.09 (1H, t, J=9.21 Hz), 7.36 (1H, brs), 7.47(1H, d, J=14.25 Hz), 7.88 (1H, m), 7.97 (1H, s), 11.67 (1H, brs). LC/MS(M+1): m/z=450.

Compound 118,N-(5-fluorobenzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide, wasprepared similarly to compound 108 except5-fluorobenzo[d]thiazol-2-amine (Sigma-Aldrich) was used in place of6-methylbenzo[d]thiazol-2-amine.

5.5 Example 5 Preparation of Compound A122(A)

2-Chloro-3-fluoro-5-vinylpyridine (112)

To a solution of 101 (5.00 g, 23.8 mmol) and4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (119, 21.39 mmol,Sigma-Aldrich) in a mixture of EtOH (30.0 mL) and THF (64.0 mL) under anargon atmosphere was added Pd(PPh₃)₂Cl₂ (1.33 g, 1.90 mmol) and K₂CO₃(8.20 g, 59.4 mmol). The resulting reaction mixture was heated to 60° C.and held for 16 hrs in a sealed bottle. The mixture was cooled to atemperature of about 25° C., diluted with water, and extracted withEtOAc. The organic layer was separated, washed with brine, andconcentrated. The residue was chromatographed on a silica gel columneluted with EtOAc:hexanes to provide 112 as a colorless oil (85% yield).¹H NMR (CDCl₃) δ: 5.48 (1H, d, J=10.97 Hz), 5.83 (1H, d, J=17.62 Hz),6.68 (1H, dd, J=10.97, 17.62 Hz), 7.52 (1H, d, J=1.60 Hz), 8.20 (1H, d,J=1.60 Hz). LC/MS (M+1): m/z=158.

Thereafter, Compound A122(a) was prepared similarly to Compound A155(a)in Example 4 except compound 120 was used in place of compound 118.

A122(a):(S)-N-(benzo[d]thiazol-2-yl)-4-(5-((S)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.24 (3H, d, J=6.6 Hz), 2.85 (1H, t, J=11.0 Hz),3.04 (1H, d, J=12.9 Hz), 3.29 (1H, m), 3.41 (1H, m, J=5.5 Hz), 3.48 (1H,m, J=5.5 Hz), 3.77 (1H, d, J=12.7 Hz), 3.93 (1H, d, J=12.5 Hz), 4.21(1H, br s), 4.52 (1H, q, J=5.0 Hz), 4.61 (1H, br s), 4.76 (1H, t, J=6.1Hz), 5.34 (1H, d, J=4.6 Hz), 7.20 (1H, t, J=6.8 Hz), 7.36 (1H, t, J=7.5Hz), 7.46 (1H, dd, J=1.8, 14.3 Hz), 7.55 (1H, br s), 7.82 (1H, br s),7.97 (1H, s), 11.37 (1H, br s). LC/MS (M+1): m/z=432.

Compound 120, N-(benzo[d]thiazol-2-yl)-1H-imidazole-1-carboxamide, wasprepared similarly to compound 108 except benzo[d]thiazol-2-amine(Sigma-Aldrich) was used in place of 6-methylbenzo[d]thiazol-2-amine.

5.6 Example 6 Preparation of Compounds A122(b), A122(c), A122(e),A123(e), A125(b), A125(e), A126(a), A126(e), A155(b), A155(d), A155(e),and A158(a)

Using procedures similar to those described in Examples 4 and 5 above,the following Compounds of Formula (I) were prepared.

A122(b): (R)-N-(benzo[d]thiazol-2-yl)-4-(5-((S)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.08 (3H, d, J=6.4 Hz), 3.11-3.70 (6H, m), 4.35-3.93(3H, m), 4.51 (1H, q, J=5.3 Hz), 4.75 (1H, t, J=5.6 Hz), 5.33 (1H, d,J=4.4 Hz), 7.20 (1H, t, J=7.5 Hz), 7.35 (1H, t, J=7.8 Hz), 7.44 (1H, d,J=14.3 Hz), 7.54 (1H, br s), 7.81 (1H, br s), 7.98 (1H, s), 11.32 (1H,br s). LC/MS (M+1): m/z=433.

A122(c):(S)-N-(benzo[d]thiazol-2-yl)-4-{5-[(S)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.08 (3H, d, J=6.6 Hz), 3.23-3.63 (6H, m), 3.90-4.21(3H, m), 4.50 (1H, t, J=5.9 Hz), 7.19 (1H, t, J=7.5 Hz), 7.35 (1H, t,J=7.5 Hz), 7.44 (1H, dd, J=1.8, 14.3 Hz), 7.52 (1H, br s), 7.80 (1H, brs), 7.98 (1H, s), 11.26 (1H, br s). LC/MS (M+1): m/z=433.

A122(e):(R)-N-(benzo[d]thiazol-2-yl)-4-(5-((R)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (CD₃OD-d₄) δ: 1.36 (3H, d, J=6.4 Hz), 2.95 (1H, m), 3.12 (1H, d,J=13.6 Hz), 3.41 (1H, m), 3.63 (2H, m), 3.89 (1H, d, J12.0 Hz), 4.03(1H, d, J=11.0 Hz), 4.67 (1H, m), 7.23 (1H, m), 7.37 (1H, m), 7.48 (2H,d, J=14.0 Hz), 7.69 (1H, br s), 8.00 (1H, s). LC/MS (M+1): m/z=432.

A123(e):(R)-N-(6-chlorobenzo[d]thiazol-2-yl)-4-(5-((R)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (CD₃OD-d₄) δ: 1.15 (3H, d, J=6.8 Hz), 2.73 (1H, t, J=10.0 Hz),2.91 (1H, d, J=14.0 Hz), 3.22 (1H, m), 3.42 (2H, m), 3.67 (1H, d, J=14.0Hz), 3.81 (1H, d, J=12.0 Hz), 4.00 (1H, m), 4.45 (1H, t, J=5.2 Hz), 7.13(1H, dt, J=2.0, 8.4 Hz), 7.25 (2H, dd, J=1.6, 14.0 Hz), 7.55 (1H, m),7.79 (1H, s). LC/MS (M+1): m/z=466.

A125(b):(R)-4-{5-[(S)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-N-(6-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.08 (3H, d, J=6.5 Hz), 3.14-3.68 (6H, m), 4.02 (1H,d, J=11.9 Hz), 4.26-4.10 (2H, m), 4.51 (1H, dd, J=5.6, 10.7 Hz), 4.74(1H, t, J5.7 Hz), 5.32 (1H, d, J=4.5 Hz), 7.21 (1H, td, J=2.6, 9.1 Hz),7.39-7.49 (1H, m), 7.51-7.60 (1H, m), 7.78 (1H, dd, J=2.4, 8.8 Hz), 7.98(1H, s), 11.37 (1H, br s). LC/MS (M+1): m/z=451.

A125(e):(R)-4-(5-((R)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-N-(6-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (CD₃OD-d₄) δ: 1.26 (3H, d, J=6.8 Hz), 2.85 (1H, dt, J=3.2, 13.0Hz), 3.02 (1H, dd, J=3.6, 13.0 Hz), 3.32 (1H, m), 3.53 (2H, m), 3.78(1H, d, J=12.0 Hz), 3.92 (1H, d, J=12.0 Hz), 4.12 (1H, m), 4.56 (1H, t,J=6.0 Hz), 7.02 (1H, dt, J=2.8, 12.0 Hz), 7.35 (1H, dd, J=1.6, 14.0 Hz),7.41 (2H, m), 7.89 (1H, s). LC/MS (M+1): m/z=450.

A126(a):(S)-4-(5-((S)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methyl-N-(6-methylbenzo[d]thiazol-2-yl)piperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.23 (3H, d, J=6.8 Hz), 2.37 (3H, s), 2.84 (1H, t,J=11.0 Hz), 3.03 (1H, dd, J=3.5, 12.1 Hz), 3.28 (1H, m), 3.41 (1H, m,J=5.5 Hz), 3.48 (1H, m, J=5.5 Hz), 3.77 (1H, d, J=12.7 Hz), 3.93 (1H, d,J=11.6 Hz), 4.19 (1H, br s), 4.52 (1H, q, J=5.3 Hz), 4.59 (1H, br s),4.75 (1H, t, J=5.3 Hz), 5.34 (1H, d, J=4.6 Hz), 7.17 (1H, d, J=7.0, Hz),7.46 (1H, d, J=13.6 Hz), 7.61 (2H, br s), 7.97 (1H, s), 11.23 (1H, brs). LC/MS (M+1): m/z=446.

A126(e):(R)-4-(5-((R)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methyl-N-(6-methylbenzo[d]thiazol-2-yl)piperazine-1-carboxamide.¹H NMR (CD₃OD-d₄) δ: 1.36 (3H, d, J=6.8 Hz), 2.43 (3H, s), 2.95 (1H, t,J=13 Hz), 3.12 (1H, dd, J=3.6, 13.0 Hz), 3.42 (1H, m), 3.64 (2H, m),3.88 (1H, d, J=13.0 Hz), 4.02 (1H, d, J=13.0 Hz), 4.2 (1H, m), 4.67 (1H,t, J=6.0 Hz), 7.19 (1H, d, J=9.2 Hz), 7.34 (1H, m), 7.46 (1H, dd, J=2.4,14.0 Hz), 7.50 (1H, m), 8.00 (1H, s). LC/MS (M+1): m/z=446.

A155(b):(R)-4-{5-[(S)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.08 (4H, d, J=6.7 Hz), 3.13-3.67 (6H, m), 3.94-4.07(1H, m), 4.07-4.28 (2H, m), 4.50 (1H, q, J=5.2 Hz), 4.75 (1H, t, J=5.7Hz), 5.33 (1H, d, J=4.4 Hz), 7.00-7.15 (1H, m), 7.38-7.50 (2H, m),7.85-8.02 (2H, m), 11.39 (1H, br s). LC/MS (M+1): m/z=451.

A155(d):(S)-4-{5-[(R)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.25 (3H, d, J=6.6 Hz), 2.83-2.93 (1H, m), 3.04 (1H,dd, J=13.0, 3.4 Hz), 3.25-3.48 (3H, m), 3.77 (1H, d, J=13.0 Hz), 3.92(1H, d, J=13.0 Hz), 4.19 (1H, d, J=13.0 Hz), 4.57-4.69 (3H, m), 5.33(1H, s), 7.08 (1H, td, J=1.5, 8.5 Hz), 7.34 (1H, d, J=8.5 Hz), 7.45 (1H,dd, J=1.5, 14.2 Hz), 7.86 (1H, dd, J=5.5, 8.5 Hz), 7.97 (1H, s), 11.63(1H, br s). LC/MS (M+1): m/z=451.

A155(e):(R)-4-{5-[(R)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-N-(5-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.24 (3H, d, J=6.7 Hz), 2.86 (1H, td, J=12.7, 3.3Hz), 3.05 (1H, dd, J=12.7, 3.3 Hz), 3.25-3.48 (3H, m), 3.74-3.79 (1H,m), 3.93 (1H, d, J=12.7 Hz), 4.19 (1H, d, J=12.7 Hz), 4.58-4.70 (3H, m),5.34 (1H, s), 7.08 (1H, dt, J=2.3, 9.1 Hz), 7.35-7.48 (2H, m), 7.84-7.96(2H, m), 11.66 (1H, br s). LC/MS (M+1): m/z=451.

A158(a):(S)-N-(5,6-difluorobenzo[d]thiazol-2-yl)-4-(5-((S)-1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.24 (3H, d, J=6.6 Hz), 2.87 (1H, t, J=12.9 Hz),3.06 (1H, d, J=10.1 Hz), 3.31 (1H, m), 3.46 (2H, m), 3.76 (1H, d, J=12.9Hz), 3.92 (1H, d, J=12.9 Hz), 4.14 (1H, d, J=12.1 Hz), 4.54 (2H, m),4.76 (1H, m), 5.35 (1H, d, J=4.2 Hz), 7.46 (1H, dd, J=1.5, 14.0 Hz),7.71 (1H, t, J=10.5 Hz), 7.97 (1H, s), 8.07 (1H, t, J=8.6 Hz), 11.40(1H, br s). LC/MS (M+1): m/z=468.

5.7 Example 7 Preparation of Compound AE

Using procedures similar to those described in Examples 4 and 5 above,the Compound AE was prepared.

AE:(R)-N-(5,6-difluorobenzo[d]thiazol-2-yl)-4-{5-[(S)-1,2-dihydroxyethyl]-3-fluoropyridin-2-yl}-3-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.08 (3H, d, J=6.6 Hz), 3.12-3.68 (6H, m), 4.00 (1H,d, J=12.4 Hz), 4.08-4.30 (2H, m), 4.51 (1H, q, J=5.3 Hz), 4.75 (1H, t,J=5.7 Hz), 5.33 (1H, d, J=4.6 Hz), 7.44 (1H, dd, J=1.8, 14.3 Hz), 7.64(1H, dd, J=7.6, 10.8 Hz), 7.94-7.99 (1H, m), 8.04 (1H, dd, J=8.0, 10.3Hz), 11.49 (1H, br s). LC/MS (M+1): m/z=469.

5.8 Example 8 Preparation of Compound A155(ad)

The following compound, Compound A155(ad), which is a racemic mixture ofthe (R)-1,2-dihydroxyethyl- and (S)-1,2-dihydroxyethyl-enantiomers, wasprepared in the same manner as in Example 4 above except for step 2 inwhich OsO₄ and NMO were used as oxidative reagents instead of AD-mixalpha.

A155(ad):(2S)-4-(5-(1,2-dihydroxyethyl)-3-fluoropyridin-2-yl)-N-(5-fluorobenzo[d]thiazol-2-yl)-2-methylpiperazine-1-carboxamide.¹H NMR (DMSO-d₆) δ: 1.24 (3H, d, J=6.6 Hz), 2.84-2.87 (1H, m), 3.03-3.06(1H, m), 3.25-3.52 (3H, m), 3.76 (1H, d, J=12.8 Hz), 3.92 (1H, d, J=12.8Hz), 4.19 (1H, d, J=12.8 Hz), 4.53-4.75 (3H, m), 5.34 (1H, d, J=4.1 Hz),7.08 (1H, t, J=8.8 Hz), 7.24-7.50 (2H, m), 7.86 (1H, br), 7.96 (1H, s),11.57 (1H, br s). LC/MS (M+1): m/z=450.

5.9 Example 9 Determination of the Optical Purity for Compound A155(e)

The % ee was determined for Compound A155(e) as shown below:

Chiral HPLC was used to determine the % ee for Compound A155(e). ACHIRALPAK 1A column (Daicel Chemical, Tokyo, Japan) was used. The peakareas for the major and minor enantiomers were determined and 94% ee wascalculated using the equation in Section 4.3.

If desired, ¹H NMR can also be used. For a ¹H NMR determination,bis-Mosher's ester derivatives are prepared for the compound(s) ofinterest, e.g., Compound A155(e), by a technique known in the art. The %ee determination is done by adding an excess of Mosher's acid chlorideto a compound of interest (about 0.6 mg) in pyridine-d⁵ (about 0.530 mL)at a temperature of about 25° C. in an NMR tube. A ¹H NMR is taken 20 hafter the addition of Mosher's acid chloride. An appropriate peak ischosen for the bis-Mosher's ester with 6 in the range from about 7.00ppm to about 6.60 ppm. It is important to note whether ¹³C satellitesare observed upfield and/or downfield of the chosen peak. The ¹H NMRpeaks for the minor and major enantiomer are integrated, the ¹³Csatellites are subtracted out, and the % ee is calculated using theequation cited above.

5.10 Example 10 Combining A Compound of Formula (I) and Fumaric Acid

To 20 mg of the free base of Compound A155(a) in 0.3±0.1 mL of MeOH in a4 mL vial at a temperature of about 25° C. was added 1.1 eq. of fumaricacid (AK Scientific). The resulting slurry was stirred with a magneticstirring bar for about 32 h. Thereafter, the slurry was evaporated todryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc.,Gardiner, N.Y.). The product was analyzed by ¹H NMR, DTA, PXRD, ¹³C NMR,and ¹⁵N NMR.

Dissolution of the product followed by ¹H NMR analysis of the resultingsolution for each component demonstrated that the average molar ratio ofCompound A155(a) to fumaric acid was about 1:0.5±0.2, with values frommultiple determinations ranging from 1:0.4 to 1:0.7.

DTA, at a rate of 10° C./minute, of the product yielded a melting onsetof 176.8° C., as determined by the temperature at which the extrapolatedmelting endotherm deviated from the extrapolated baseline, and a meltingpoint of 182.9° C., as determined by the temperature at the meltingendotherm peak. In contrast, for Compound A155(a) similarly-crystallizedto anhydrate crystals from MeOH but in the absence of fumaric acid, theDTA melting onset was 185.7° C. and the DTA melting point was 189.4° C.

Powder x-ray diffraction intensity data were collected on a Bruker D8Discover apparatus using CuKα radiation (λ=1.5418 Å). The scanning rangewas from 3.0° to 40° 2θ. The reported 2θvalues are ±0.2° 2θ. FIG. 1provides the PXRD pattern and Table 4 summarizes the peaks observed forthe product prepared with fumaric acid as described above while Table 5summarizes the peaks observed for crystalline anhydrate (i.e., freebase) Compound A155(a). For each table, peak maximum relative intensityis denoted as follows: VS=very strong, S=strong, M=medium, and W=weak.

TABLE 4 Powder X-ray Diffraction Results for Product Position Relative[°2θ] Intensity 5.8 W 6.5 S 8.6 M 9.3 W 10.8 W 12.5 S 14.0 M 16.8 VS18.7 M 19.7 W 20.4 M 21.3 M 22.0 M 23.2 S 25.3 S 26.8 W 28.2 W 28.5 W30.8 W 35.0 W 38.5 S

TABLE 5 Powder X-ray Diffraction Results for Compound A155(a) PositionRelative [°2θ] Intensity 13.5 W 15.8 W 17.5 W 18.5 W 20.3 M 22.6 S 23.2M 24.7 VS 26.1 M 26.9 S 27.8 M 36.3 W 38.7 M

All solid-state cross polarization magic angle spinning (CP/MAS) NMRdeterminations were performed on a Varian NMR System 600 MHz NMRspectrometer (Varian NMR, Inc., Palo Alto, Calif.) with a 3.2 mmrotor-outside-diameter probe at a frequency of 150.8 MHz, for ¹³C, and60.79 MHz, for ¹⁵N. Sample temperature was controlled at 10° C.±0.2° C.The ¹⁵N spectra were measured under the following conditions: spectralwidth of 24,510 Hz, acquisition time of 40 ms, recycle delay time offrom 5 s to 15 s, contact time of 2 ms, ¹⁵N π/2 pulse lengths of 4.2 μs,1H π/2 pulse lengths of 2.2 μs. As a reference, ¹⁵N glycine at δ of−347.54 was used. The ¹³C spectra were measured under the followingconditions: spectral width of 43,103 Hz, acquisition time of 40 ms,recycle delay time of 10 s, contact time of 3 ms, ¹³C π/2 pulse lengthsof 2.0 μs, 1H π/2 pulse lengths of 2.2 μs. As a reference, the ¹³C themethylene peak of adamantane at δ of 38.52 was used. For the purposes ofthe ¹³C NMR and ¹⁵N NMR analyses, the non-hydrogen atoms of CompoundA155(a) are identified as follows:

¹⁵N NMR CP/MAS spectra of the product prepared with Compound A155(a) andfumaric acid, the dihydrochloride-salt of Compound A155(a), and the freebase of Compound A155(a) are shown in FIG. 2. Significant differences inthe shapes and/or chemical shifts of the N-3 and N-25 peaks can be notedbetween the spectrum of the free base of Compound A155(a) and thedihydrochloride-salt of Compound A155(a), which differences are believedto be attributable to the ionic nature of the salt formed with each ofthese nitrogen atoms in the dihydrochloride-salt. In contrast, theshapes and/or chemical shifts of the N-3 and N-25 peaks in the spectraof the free base of Compound A155(a) and the product prepared withCompound A155(a) and fumaric acid are far more similar, the chemicalshifts differing by only less than about 12 ppm. It is believed that itsco-crystalline nature is demonstrated by the lack of significantionization of the N-3 and N-25 nitrogen atoms in the product preparedwith Compound A155(a) and fumaric acid.

A ¹³C NMR CP/MAS spectrum of the product prepared with Compound A155(a)and fumaric acid is shown in FIG. 3. The chemical shifts in thisspectrum are clearly different from the chemical shifts of the free baseof Compound A155(a) (not shown). Additionally, new peaks (at about171.5, 170.3 and/or 135.6 ppm) attributable to the presence of fumarateco-crystal are evident which differ from peaks of fumaric acid in itsfree form; these new peaks are denoted by the five-pointed stars in FIG.3 and are believed to be indicative of the co-crystalline nature of theproduct.

In one embodiment, the product prepared with Compound A155(a) andfumaric acid has a melting onset of from about 175° C. to about 179° C.when measured using DTA at a rate of 10° C./min. In another embodiment,the product prepared with Compound A155(a) and fumaric acid has amelting onset of from about 175.5° C. to about 178.5° C. when measuredusing DTA at a rate of 10° C./min. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has a melting onset offrom about 176° C. to about 178° C. when measured using DTA at a rate of10° C./min. In another embodiment, the product prepared with CompoundA155(a) and fumaric acid has a melting onset of from about 176.4° C. toabout 177.2° C. when measured using DTA at a rate of 10° C./min. Inanother embodiment, the product prepared with Compound A155(a) andfumaric acid has a melting onset of about 176.8 when measured using DTAat a rate of 10° C./min.

In one embodiment, the product prepared with Compound A155(a) andfumaric acid has a melting point of from about 181° C. to about 185° C.when measured using DTA at a rate of 10° C./min. In another embodiment,the product prepared with Compound A155(a) and fumaric acid has amelting point of from about 181.5° C. to about 184.5° C. when measuredusing DTA at a rate of 10° C./min. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has a melting point offrom about 182° C. to about 184° C. when measured using DTA at a rate of10° C./min. In another embodiment, the product prepared with CompoundA155(a) and fumaric acid has a melting point of from about 182.5° C. toabout 183.3° C. when measured using DTA at a rate of 10° C./min. Inanother embodiment, the product prepared with Compound A155(a) andfumaric acid has a melting point of about 182.9° C. when measured usingDTA at a rate of 10° C./min.

In one embodiment, the product prepared with Compound A155(a) andfumaric acid has an x-ray powder diffraction pattern comprising a peakat each of 6.5°, 12.5°, 16.8°, and 25.3° 2θ±0.2° 2θ when measured usingCuKα radiation. In another embodiment, the product prepared withCompound A155(a) and fumaric acid has an x-ray powder diffractionpattern comprising a peak at each of 6.5°, 12.5°, 16.8°, 23.2°, 25.3°,and 38.5° 2θ±0.2° 2θ when measured using CuKα radiation. In anotherembodiment, the product prepared with Compound A155(a) and fumaric acidhas an x-ray powder diffraction pattern comprising a peak at each of6.5°, 8.6°, 12.5°, 14.0°, 16.8°, 18.7°, and 25.3° 2θ±0.2° 2θ whenmeasured using CuKα radiation. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has an x-ray powderdiffraction pattern comprising a peak at each of 6.50, 8.6°, 12.5°,14.0°, 16.8°, 18.7°, 20.4°, 21.3°, 22.0°, 23.2°, 25.3°, and 38.5°2θ±0.2° 2θ when measured using CuKα radiation.

In one embodiment, the product prepared with Compound A155(a) andfumaric acid has a CP/MAS ¹³C NMR spectrum comprising peaks with achemical shift of 170.3±0.2 ppm, 130.0±0.2 ppm, and 72.2±0.2 ppm. Inanother embodiment, the product prepared with Compound A155(a) andfumaric acid has a CP/MAS ¹³C NMR spectrum comprising peaks with achemical shift of 171.5±0.2 ppm, 170.3±0.2 ppm, 130.0±0.2 ppm, and72.2±0.2 ppm. In another embodiment, the product prepared with CompoundA155(a) and fumaric acid has a CP/MAS ¹³C NMR spectrum comprising peakswith a chemical shift of 171.5±0.2 ppm, 170.3±0.2 ppm, 130.0±0.2 ppm,72.2±0.2 ppm, and 15.1±0.2 ppm. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has a CP/MAS ¹³C NMRspectrum comprising peaks with a chemical shift of 170.3±0.2 ppm,135.6±0.2 ppm, and 72.2±0.2 ppm. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has a CP/MAS ¹³C NMRspectrum comprising peaks with a chemical shift of 171.5±0.2 ppm,170.3±0.2 ppm, and 135.6±0.2 ppm. In another embodiment, the productprepared with Compound A155(a) and fumaric acid has a CP/MAS ¹³C NMRspectrum comprising peaks with a chemical shift of 171.5±0.2 ppm,170.3±0.2 ppm, 135.6±0.2 ppm, and 72.2±0.2 ppm. In another embodiment,the product prepared with Compound A155(a) and fumaric acid has a CP/MAS¹³C NMR spectrum comprising peaks with a chemical shift of 171.5±0.2ppm, 170.3±0.2 ppm, 135.6±0.2 ppm, 72.2±0.2 ppm, and 15.1±0.2 ppm.

Alternately, 1.0 g of the free base of Compound A155(a) in 20 mL of MeOHat a temperature of about 25° C. was stirred with a magnetic stirringbar. Then, 1.1 eq. of fumaric acid was added, the resulting suspensionwas stirred with a magnetic stirring bar until dissolution appearedcomplete, a seed crystal of the product prepared from Compound A155(a)and fumaric acid was added, and stirring continued while a precipitateformed. Thereafter, the precipitate was filtrated and dried underreduced pressure to provide a product that, upon PXRD analysis, yieldedsubstantially the same PXRD results as provided in FIG. 1 and Table 4.

5.11 Example 11 Combining a Compound of Formula (I) and HydrochloricAcid

To 0.3±0.1 mL of MeOH in a 4 mL vial also containing molecular sievedrying agent is added 1.1 eq. of concentrated hydrochloric acid. Theresulting mixture is stirred with a magnetic stirring bar for about 1 h.The molecular sieves are filtered off. Thereafter, 20 mg of a Compoundof Formula (I) is added. The resulting slurry is stirred with a magneticstirring bar for about 32 h. Thereafter, the slurry is evaporated todryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc.,Gardiner, N.Y.). The residue product is analyzed by ¹H NMR, DTA, andPXRD as described in Example 10.

5.12 Example 12 Combining a Compound of Formula (I) and Tartaric Acid

To 20 mg of a Compound of Formula (I) in 0.3±0.1 mL of MeOH in a 4 mLvial is added 1.1 eq. of tartaric acid, i.e., 2,3-dihydroxysuccinic acid(Sigma-Aldrich). The resulting slurry is stirred with a magneticstirring bar for about 32 h. Thereafter, the slurry is evaporated todryness using a centrifugal evaporator (HT-8 Series II, Genevac Inc.,Gardiner, N.Y.). The residue product is analyzed by ¹H NMR, DTA, andPXRD as described in Example 10.

5.13 Example 13 Combining a Compound of Formula (I) and BenzenesulfonicAcid

To 20 mg of a Compound of Formula (I) in 0.3±0.1 mL of MeOH in a 4 mLvial is added 1.1 eq. of benzenesulfonic acid (Sigma-Aldrich). Theresulting slurry is stirred with a magnetic stirring bar for about 32 h.Thereafter, the slurry is evaporated to dryness using a centrifugalevaporator (HT-8 Series II, Genevac Inc., Gardiner, N.Y.). The residueproduct is analyzed by ¹H NMR, DTA, and PXRD as described in Example 10.

5.14 Example 14 Combining a Compound of Formula (I) and ToluenesulfonicAcid

To 20 mg of a Compound of Formula (I) in 0.3±0.1 mL of MeOH in a 4 mLvial is added 1.1 eq. of toluenesulfonic acid, i.e.,4-methylbenzenesulfonic acid (Sigma-Aldrich). The resulting slurry isstirred with a magnetic stirring bar for about 32 h. Thereafter, theslurry is evaporated to dryness using a centrifugal evaporator (HT-8Series II, Genevac Inc., Gardiner, N.Y.). The residue product isanalyzed by ¹H NMR, DTA, and PXRD as described in Example 10.

5.15 Example 15 Binding of Compounds of Formula (I) to TRPV1

Methods for assaying compounds capable of inhibiting TRPV1 are known inthe art, for example, those methods disclosed in U.S. Pat. No. 6,239,267to Duckworth et al., U.S. Pat. No. 6,406,908 to McIntyre et al., or U.S.Pat. No. 6,335,180 to Julius et al. The results of these assays willdemonstrate that Compounds of Formula (1) bind to and modulate theactivity of TRPV1.

Protocol 1

Human TRPV1 Cloning:

Human spinal cord RNA (commercially available from Clontech, Palo Alto,Calif.) is used. Reverse transcription is conducted on 1.0 μg total RNAusing Thermoscript Reverse Transcriptase (commercially available fromInvitrogen, Carlsbad, Calif.) and oligo dT primers as detailed in itsproduct description. Reverse transcription reactions are incubated at55° C. for 1 h, heat-inactivated at 85° C. for 5 min, and RNaseH-treated at 37° C. for 20 min.

Human TRPV1 cDNA sequence is obtained by comparison of the human genomicsequence, prior to annotation, to the published rat sequence. Intronsequences are removed and flanking exonic sequences are joined togenerate the hypothetical human cDNA. Primers flanking the coding regionof human TRPV1 are designed as follows: forward primerGAAGATCTTCGCTGGTTGCACACTGGGCCACA (SEQ ID NO: 1), and reverse primerGAAGATCTTCGGGGACAGTGACGGTTGGATGT (SEQ ID NO: 2).

Using these primers, PCR of TRPV1 is performed on one tenth of theReverse transcription reaction mixture using Expand Long TemplatePolymerase and Expand Buffer 2 in a final volume of 50 μL according tothe manufacturer's instructions (Roche Applied Sciences, Indianapolis,Ind.). After denaturation at 94° C. for 2 min PCR amplification isperformed for 25 cycles at 94° C. for 15 sec, 58° C. for 30 sec, and 68°C. for 3 min followed by a final incubation at 72° C. for 7 min tocomplete the amplification. The PCR product of about 2.8 kb isgel-isolated using a 1.0% agarose, Tris-Acetate gel containing 1.6 μg/mLof crystal violet and purified with a S.N.A.P. UV-Free Gel PurificationKit (commercially available from Invitrogen). The TRPV1 PCR product iscloned into the pIND/V5-His-TOPO vector (commercially available fromInvitrogen) according to the manufacturer's instructions to result inthe TRPV1-pIND construct. DNA preparations, restriction enzymedigestions, and preliminary DNA sequencing are performed according tostandard protocols. Full-length sequencing confirms the identity of thehuman TRPV1.

Generation of Inducible Cell Lines:

Unless noted otherwise, cell culture reagents are purchased from LifeTechnologies of Rockville, Md. HEK293-EcR cells expressing the ecdysonereceptor (commercially available from Invitrogen) are cultured in GrowthMedium (Dulbecco's Modified Eagles Medium containing 10% fetal bovineserum (commercially available from Hyclone, Logan, Utah)), 1×penicillin/streptomycin, 1× glutamine, 1 mM sodium pyruvate and 400μg/mL Zeocin (commercially available from Invitrogen)). The TRPV1-pINDconstructs are transfected into the HEK293-EcR cell line using Fugenetransfection reagent (commercially available from Roche AppliedSciences, Basel, Switzerland). After 48 h, cells are transferred toSelection Medium (Growth Medium containing 300 μg/mL G418 (commerciallyavailable from Invitrogen)). Approximately 3 weeks later individualZeocin/G418 resistant colonies are isolated and expanded. To identifyfunctional clones, multiple colonies are plated into 96-well plates andexpression is induced for 48 h using Selection Medium supplemented with5 μM ponasterone A (“PonA”) (commercially available from Invitrogen). Onthe day of assay, cells are loaded with Fluo-4 (a calcium-sensitive dyethat is commercially available from Molecular Probes, Eugene, Oreg.) andCAP-mediated calcium influx is measured using a Fluorescence ImagingPlate Reader (“FLIPR”) as described below. Functional clones arere-assayed, expanded, and cryopreserved.

pH-Based Assay:

Two days prior to performing this assay, cells are seeded onpoly-D-lysine-coated 96-well clear-bottom black plates (commerciallyavailable from Becton-Dickinson) at 75,000 cells/well in growth mediacontaining 5 μM PonA (commercially available from Invitrogen) to induceexpression of TRPV1. On the day of the assay, the plates are washed with0.2 mL 1× Hank's Balanced Salt Solution (commercially available fromLife Technologies) containing 1.6 mM CaCl₂ and 20 mM HEPES, pH 7.4(“wash buffer”), and loaded using 0.1 mL of wash buffer containingFluo-4 (3 μM final concentration, commercially available from MolecularProbes). After 1 h, the cells are washed twice with 0.2 mL wash bufferand resuspended in 0.05 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 3.5 mM CaCl₂and 10 mM Citrate, pH 7.4 (“assay buffer”). Plates are then transferredto a FLIPR for assay. The test compound is diluted in assay buffer, and50 μL of the resultant solution is added to the cell plates and thesolution is monitored for two minutes. The final concentration of thetest compound is adjusted to range from about 50 picoM to about 3 μM.Agonist buffer (wash buffer titrated with 1N HCl to provide a solutionhaving a pH of 5.5 when mixed 1:1 with assay buffer) (0.1 mL) is thenadded to each well, and the plates are incubated for 1 additionalminute. Data are collected over the entire time course and analyzedusing Excel and Graph Pad Prism to determine the IC₅₀.

Capsaicin-Based Assay:

Two days prior to performing this assay, cells are seeded inpoly-D-lysine-coated 96-well clear-bottom black plates (50,000cells/well) in growth media containing 5 μM PonA (commercially availablefrom Invitrogen) to induce expression of TRPV1. On the day of the assay,the plates are washed with 0.2 mL 1× Hank's Balanced Salt Solution(commercially available from Life Technologies) containing 1 mM CaCl₂and 20 mM HEPES, pH 7.4, and cells are loaded using 0.1 mL of washbuffer containing Fluo-4 (3 μM final). After one hour, the cells arewashed twice with 0.2 mL of wash buffer and resuspended in 0.1 mL ofwash buffer. The plates are transferred to a FLIPR for assay. 50 μL oftest compound diluted with assay buffer (1× Hank's Balanced SaltSolution containing 1 mM CaCl₂ and 20 mM HEPES, pH 7.4) are added to thecell plates and incubated for 2 min. The final concentration of thecompound is adjusted to range from about 50 picoM to about 3 μM. HumanTRPV1 is activated by the addition of 50 μL of capsaicin (400 nM), andthe plates are incubated for an additional 3 min. Data are collectedover the entire time course and analyzed using Excel and GraphPad Prismto determine the IC₅₀.

Protocol 2

For Protocol 2, a Chinese Hamster Ovary cell line (CHO) that has beenengineered to constitutively express human recombinant TRPV1 was used(TRPV1/CHO cells). The TRPV1/CHO cell line was generated as describedbelow.

Human TRPV1 Cloning:

A cDNA for the human TRPV1 receptor (hTRPV1) was amplified by PCR(KOD-Plus DNA polymerase, ToYoBo, Japan) from a human brain cDNA library(BioChain) using primers designed surrounding the complete hTRPV1 openreading frame (forward 5′-GGATCCAGCAAGGATGAAGAAATGG (SEQ ID NO: 3) andreverse 5′-TGTCTGCGTGACGTCCTCACTTCT (SEQ ID NO: 4)). The resulting PCRproducts were purified from agarose gels using Gel Band Purification Kit(GE Healthcare Bioscience) and were subcloned into pCR-Blunt vector(Invitrogen). The cloned cDNA was fully sequenced using a fluorescentdye-terminator reagent (BigDye Terminator ver3.1 Cycle Sequencing Kit,Applied Biosystems) and ABI Prism 3100 genetic analyzer (AppliedBiosystems). The pCR-Blunt vector containing the hTRPV1 cDNA wassubjected to restriction digestion with EcoR1. The restriction fragmentwas subcloned into expression vector pcDNA3.1(−) (Invitrogen) and namedpcDNA3.1(−)-hVR1 plasmid. The sequence of the cDNA encoding TRPV1 isavailable at GenBank accession number AJ277028.

Generation of the TRPV1/CHO Cell Line:

CHO-K1 cells were maintained in growth medium consisting of α-MEM, 10%FBS (Hyclone), and 100 IU/mL of penicillin—100 μg/mL of streptomycinmixed solution (Nacalai Tesque, Japan) at 37° C. in an environment ofhumidified 95% air and 5% CO₂. The cells were transfected with thepcDNA3.1(−)-hVR1 plasmid using FuGENE6 (Roche) according to themanufacturer's protocol. 24 hr after transfection, neomycin-resistantcells were selected using 1 mg/mL G418 (Nacalai Tesque). After 2 weeks,individual colonies were picked, expanded, and screened for theexpression of hTRPV1 in the capsaicin-induced Ca²⁺ influx assay (seebelow) with a FLIPR (Molecular Devices). A clone with the largest Ca²⁺response to capsaicin was selected and re-cloned by the same procedure.The cells expressing hTRPV1 were cultured in the growth mediumsupplemented with 1 mg/mL G418. Approximately 1 month later, stableexpression of functional TRPV1 receptors in the selected cell line wasconfirmed by validating Ca²⁺ responses with or without capsazepine(Sigma, at 1 nM-10 μM) in capsaicin assay.

Capsaicin-Induced Ca²⁺ Influx Assay for Cell Selection:

The following assay was performed to identify cells with hTRPV1expression. CHO-K1 cells transfected with pcDNA3.1(−)-hVR1 plasmid wereseeded in 384-well black-wall clear-bottom plates (Corning) andcultivated in growth medium (see above) for 1 day. On the day of theexperiment, culture medium was exchanged to assay buffer (20 mM HEPES,137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl₂, 5.0 mM CaCl₂, 5.6 mM D-glucose,2.5 mM probenecid, pH 7.4) containing 4 μM Fluo-3-AM (Dojin, Japan).After the incubation at 37° C. for 1 hr, each well was washed 3 timeswith assay buffer using an EMBLA 384 plate washer (Molecular Devices)and refilled with assay buffer. The plates were incubated at atemperature of about 25° C. for 10 min. Subsequently, the plates wereinserted into a FLIPR, and 1.5 μM capsaicin (Sigma) solution prepared inassay buffer was added to each well (final concentration was 500 nM).Cellular responses were monitored for 5 min.

Cell Culture:

1. Cell Culture Media

1. Alpha-MEM (Gibco, CAT: 12561-056, LOT: 1285752): 450 mL.

2. Fetal Bovine Serum (FBS), heat inactivated (Gibco, CAT: 16140-071,LOT: 1276457): 50 mL.

3. HEPES Buffer Solution, 1M stock (Gibco, CAT: 15630-080): 10 mL (final20 mM).

4. Geneticin, 50 mg/mL stock (Gibco, CAT: 10135-035): 10 mL (final 1mg/mL).

5. Antimicotic Antibiotic Mixed Solution, 100× stock (Nacalai Tesque,CAT: 02892-54): 5 mL.

Components 1-5 above were combined at the indicated amounts and storedat 4° C. The cell culture media were brought to about 37° C. before use.Optionally, component 5 can be replaced by penicillin-streptomycinsolution (for example, Gibco 15140-122 or Sigma P-0781).

2. Thawing the Cells

TRPV1/CHO cells were frozen in CELLBANKER™ (Juji-Field, Inc., Japan,CAT: BLC-1) and stored at −80° C. Optimized cryopreservation solutioncontaining dimethyl sulfoxide and FBS was used.

Vials containing the TRPV1/CHO cells were stored at −80° C. Afterremoval from −80° C., the vial was immediately transferred to a 37° C.water bath to thaw for ca. 1-2 minutes. Once completely thawed, thecontents of the vial (1 mL/vial) was transferred to a sterile 15 mL testtube and 9 mL warm culture media were slowly added. The test tube wassubsequently centrifuged at 1000 rpm for 4 min at a temperature of about25° C. The supernatant was removed and the pellet resuspended in 10 mLof culture media. The cell suspension was transferred to a sterile 75cm² plastic flask and incubated at humidified 5% CO₂/95% air at 37° C.To monitor viability, the cells were visually inspected and/or counted,beginning at approximately 1 hr after incubation.

3. Passaging the Cells

The cells in a flask were close to confluence at the time of passaging.Cell culture media were removed from the culture flask and 10 mL ofsterile PBS(−) added and the flask gently shaken. The PBS was removedfrom the flask and 2 mL of trypsin/EDTA solution (0.05% trypsin withEDTA-4Na; Gibco, CAT: 25300-054) was added and the flask gently shaken.The flask was incubated at 37° C. for about 2 min. 8 mL cell culturemedia were subsequently added to the flask and the flask shaken toensure that all cells were in solution. The cell suspension was thentransferred to a sterile 15 mL or 50 mL plastic tube, centrifuged at1,000 rpm for 4 min at a temperature of about 25° C. The supernatant wasremoved and the pellet resuspended in ca. 5 mL of culture media. Thecell count was measured using the Burker-Turk hemocytometer.

The cells were seeded into a sterile 75 cm² plastic flask in ca. 0.8×10⁵cells/mL for 72 hr and incubated in humidified 5% CO₂/95% air at 37° C.

4. Freezing the Cells

The procedure up to the measurement of the cell count was the same as inthe Section entitled “Passaging the Cells” above. Subsequently, the cellsuspension was centrifuged at 1,000 rpm for 4 min at a temperature ofabout 25° C. The supernatant was removed and the pellet resuspended inCELLBANKER™ solution to get a final concentration of from 5×10⁵ to 5×10⁶cells/mL. The cell suspension was transferred into appropriately labeled1 mL cryovials and then placed into the −80° C. freezer.

pH-Based Assay:

The following assay was conducted to determine the concentration ofsulfuric acid that would give rise to a pH that induces a Ca²⁺ responseoptimal to test compounds for their effect on TRPV1.

1. Cells

TRPV1/CHO cells were seeded in the 96-well clear-bottom black-wall plate(Nunc) at densities of 1-2×10⁴ cells/well and grown in 100 μL of culturemedium (alpha-MEM supplemented with 10% FBS, 20 mM HEPES, 1 mg/mLgeneticin and 1% antibiotic-antimycotic mixed stock solution) for 1-2days before the experiment.

2. Determination of pH Sensitivity and Agonist Dose

2.1. Agonist Solution

Seven different agonist solutions with sulfuric acid concentrations of15.0, 15.5, 16.0, 16.5, 17.0, 17.5, and 18.0 mM were prepared bydiluting 1M sulfuric acid with measuring buffer (see, e.g., FIG. 1 ofU.S. Patent Application Publication No. US 2009/0170868 A1). Thedifferent sulfuric acid concentrations in the agonist solutions wereselected such that a 1:4 dilution would result in a final sulfuric acidconcentration of 3.0, 3.1, 3.2, 3.3, 3.4, 3.5, and 3.6 mM, denoted “B”through “H” respectively. Buffer without sulfuric acid, denoted “A”, wasalso used.

2.2. Assay

pH dependent Ca²⁺ responses in TRPV1/CHO cells cultured in a 96-wellplate were determined (see, e.g., FIG. 2 of U.S. Patent ApplicationPublication No. US 2009/0170868 A1). In particular, Ca²⁺ influx intoTRPV1/CHO cells in response to low pH as measured by Fura-2 AMfluorescence was determined. The cells were stimulated using 3.0 mM(well numbers B1-B6), 3.1 mM (C1-C6), 3.2 mM (D1-D6), 3.3 mM (E1-E6),3.4 mM (F1-F6), 3.5 mM (G1-G6), or 3.6 mM (H1-H6) H₂SO₄ or pH 7.2measuring buffer without H₂SO₄ (A1-A6).

(1) Culture medium was removed using an 8-channel-pipette (Rainin, USA)from the 96-well plate and the wells were refilled with 100 μL ofloading buffer (20 mM HEPES, 115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂, 1.8mM CaCl₂, 13.8 mM D-glucose, 2.5 mM probenecid, pH 7.4) containing 5 μMFura-2 AM (Dojin, Japan).

(2) The 96-well plate was incubated at 37° C. for 45 min.

(3) The loading buffer was removed from each well. The cells weresubsequently washed twice with 150 μL of measuring buffer (20 mM HEPES,115 mM NaCl, 5.4 mM KCl, 0.8 mM MgCl₂, 5.0 mM CaCl₂, 13.8 mM D-glucose,0.1% BSA, pH 7.4) (no probenecid). The wells were then refilled with 80μL of measuring buffer.

(4) After an incubation at 4° C. for 15 min, the 96-well plate wastransferred to a model FDSS-3000 plate reader apparatus (HamamatsuPhotonics K.K., Japan).

(5) The Fura-2 fluorescent intensity was monitored at a wavelength of340 nm and at 380 nm, respectively, at a rate of 0.5 Hz for a total of240 seconds. After 16 time points (32 sec) of baseline detection, 20 μLof agonist solution was added to each well. The final volume was 100μL/well.

(6) Fluorescence intensity ratio refers to the fluorescence intensity at340 nm over the fluorescence intensity at 380 nm at a particular timepoint. The baseline was set as the average of the fluorescent intensityratios for the first 16 time points before the addition of agonistsolution. The maximum response was the highest fluorescent intensityratio during the 60 time points following addition of agonist solution.

(7) Maximal signal ratios from each well were calculated as output datausing the FDSS-3000 analysis program. Data were analyzed using Excel(Microsoft) and XLfit (idbs) software.

2.3. pH Determination

After the observation of Ca²⁺ responses, the buffer of each lane of the96-well plate (50 μL/well, 8-20 wells/plate) was collected well by welland the pH values were measured using a portable pH meter (Shindengen,Japan).

The Ca²⁺ responses in lanes D and E were intermediate and thereforeoptimal for testing the effects of compounds on the TRPV1 calciumchannel (see, e.g., FIG. 2 of U.S. Patent Application Publication No. US2009/0170868 A1). The final sulfuric acid concentrations in the wells ofthese lanes were 3.2 mM and 3.3 mM, respectively. These final sulfuricacid concentrations were obtained using agonist solutions with 16.0 mMand 16.5 mM sulfuric acid concentrations, respectively (lanes D and E).The pH obtained using these sulfuric acid concentrations was from about5.0 to about 5.1.

Thus, agonist solutions with 16.0 mM and 16.5 mM sulfuric acidconcentrations, respectively (lanes D and E), were selected for theexperiments described below in Section 3.

3. pH Assay

3.1. Agonist

In an “agonist plate,” two different agonist solutions with differentH₂SO₄ concentrations were used for the pH assay (see, e.g., FIG. 3A ofU.S. Patent Application Publication No. US 2009/0170868 A1). For thefirst half of a 96-well plate one agonist solution was used; for thesecond half the other agonist solution was used. The agonist solutionswere obtained by diluting sulfuric acid (1M H₂SO₄) with measuringbuffer. The concentrations for the two agonist solutions were determinedas described above in Section 2 of Protocol 2.

The sulfuric acid concentrations between the two agonist solutionsdiffered by 0.5 mM. In the experiment described in Section 2 of Protocol2, the sulfuric acid concentrations in the agonist solutions weredetermined to be 16 mM and 16.5 mM, respectively. After 1:4 dilution ofthe agonist solutions, the final sulfuric acid concentration was 3.2 mMand 3.3 mM, respectively. The resulting pH value for the pH assay was5.0 to 5.1.

3.2. Test Compounds

Test compounds were dissolved in DMSO to yield 1 mM stock solutions. Thestock solutions were further diluted using DMSO in 1:3 serial dilutionsteps with 6 points (1000, 250, 62.5, 15.625, 3.9062, and 0.977 μM). Thethereby-obtained solutions were further diluted in measuring buffer(1:100) as 10× stock serial dilutions with a DMSO concentration of 1%.10 μL of a 100× stock was added into each well of an “antagonist plate”(see step 3.3.(4) below). Thus, the final concentrations of antagonistswas as follows: 0.977, 3.906, 15.63, 62.5, 250, and 1000 nM containing0.1% DMSO (see, e.g., FIG. 3B of U.S. Patent Application Publication No.US 2009/0170868 A1).

3.3. Assay

Steps (1) and (2) of this Assay were the same as steps 2.2.(1) and2.2.(2), respectively, of Protocol 2.

(3) The cells were washed twice with 150 μL of measuring buffer(mentioned in step 2.2.(3) of Protocol 2, no probenecid). The wells weresubsequently refilled with 70 μL of measuring buffer.

(4) Either 10 μL of measuring buffer or 10 μL of 10× stock serialdilution of test compound (described in step 3.2. above) were applied toeach well. Usually, only one test compound was tested per 96-well plate.The number of replicates per 96-well plate for a particular antagonistat a particular concentration was 2×7 since, as described for the“agonist plate,” two different sulfuric acid concentrations were usedper 96-well plate and seven lanes (A-C, E-H) per 96-well plate were used(N=2×7).

Step (5) was the same as step 2.2.(4) above.

(6) Fura-2 fluorescent intensity was monitored as described in step2.2.(5) above. After 16 time points of baseline detection, 20 μL ofagonist solution (measuring buffer titrated with H₂SO₄ to yield a pH inthe range of from about 5.0 to about 5.1 when mixed 1:4 with themeasuring buffer containing test compound) was added to each well (finalvolume 100 μL/well).

Steps (7) and (8) were as described in steps 2.2.(6) and 2.2.(7) above,respectively.

3.4. pH Check

(1) The pH values of the buffer in the wells of A1 through H1 and A7through H7 were measured one by one using a portable pH meter.

(2) When a well was confirmed as having a pH of from about 5.0 to about5.1, the next five wells to its right (e.g., for well B1, wells B2through B6) were checked one after another.

(3) For IC₅₀ calculation, only the data from wells with pH values of5.0-5.1 were used.

The number of wells tested for their pH varied among plates (from about16 to 60 wells/plate). The number depended on the results of step3.4.(1) above and the Ca²⁺ responses.

Capsaicin-Based Assay:

One day prior to assay, TRPV1/CHO cells were seeded in 96-wellclear-bottom black plates (20,000 cells/well) in growth media. On theday of the experiment, the cells were washed with 0.2 mL 1× Hank'sBalanced Salt Solution (Life Technologies) containing 1.6 mM CaCl₂ and20 mM HEPES, pH 7.4 (“wash buffer”). Subsequently, the cells were loadedby incubation in 0.1 mL of wash buffer containing Fluo-4 at 3 μM finalconcentration. After 1 hour, the cells were washed twice with 0.2 mLwash buffer and resuspended in 0.1 mL wash buffer. The plates were thentransferred to a Fluorescence Imaging Plate Reader (Molecular Devices).Fluorescence intensity was monitored for 15 seconds to establish abaseline. Subsequently, test compounds diluted in assay buffer (1×Hank's Balanced Salt Solution containing 1 mM CaCl₂ and 20 mM HEPES, pH7.4) containing 1% DMSO were added to the cell plate and fluorescencewas monitored for 2 minutes. The final concentration of the compound wasadjusted to range from 100 μM to 1.5625 μM. If the test compound was anespecially potent antagonist, the final concentration of the compoundwas adjusted to range from 10 μM to 1.5625 nM. Human TRPV1 was thenactivated by the addition of 50 μL capsaicin (100 nM finalconcentration) and plates incubated for an additional 3 min. Data werecollected over the entire time course and analyzed using Excel and thecurve-fitting formula GraphPad Prism.

The results of the assays of Protocol 2 are shown in Table 6.

Human TRPV1 Heat-Based Assay:

CHO cells stably expressing human TRPV1 (hTRPV1) were used. Functionalassessment of heat-induced activation of hTRPV1 was carried out in acell-based Ca²⁺ flux assay using ABI7500 Fast Real-Time PCR System asdescribed in Reubish et al., “Functional assessment of temperature-gatedion-channel activity using a real-time PCR machine,”www.BioTechniques.com 47(3):iii-ix (2009), which is hereby incorporatedby reference. Briefly, hTRPV1/CHO cells were cultured in growth media ina tissue culture dish at 37° C. in a CO₂ incubator. On the day of theassay, culture media were removed and the cells were then detached using0.05% trypsin at 37° C. with 5% CO₂, for 90 s. The detached cells werecentrifuged (1000 rpm, 4 min) to remove trypsin-containing supernatantand resuspended in assay buffer (115 mM NaCl, 5.4 mM KCl, 0.8 mMMgCl₂.6H₂O, 1.8 mM CaCl₂ 2H₂O, 13.8 mM D-glucose, and 20 mM HEPES).Then, the cells were loaded with 5 μM Fluo-4, a Ca²⁺ reporter dye, inthe presence of 2.5 mM probenecid at 37° C. with 5% CO₂, for 45 min.Thereafter, the cells were washed twice with measuring buffer (assaybuffer supplemented with 0.1% BSA and 3.2 mM CaCl₂) then transferred toa Fast 96-well Reaction Plate (0.1 mL) (Part no. 4346907, MICROAMP,Applied Biosystems, Foster City, Calif.). The cell density was 100,000cells/24 μL/well. A solution of the compound under test (6 μL/well) wasadded into each well of the 96-well plate. Thus, the reaction volume perwell was 30 μL.

The plates were then placed inside an ABI7500 Fast Real-Time PCRinstrument (Applied Biosystems) to read fluorescence at differenttemperatures using 7500 software, version 2.0.2 (Applied Biosystems).The initial temperature was set at 25° C. for 1 min. followed by atemperature ramp to 45° C. in 100 s to deliver heat to cells. [Ca²⁺];response of hTRPV1/CHO cells to heat was determined as:[fluorescence read at 45° C.−fluorescence read at 25° C.].

Compound concentration response curves and IC₅₀ values were analyzedusing GraphPad Prism 4 software (GraphPad Software, La Jolla, Calif.).

The IC₅₀ data provided in Table 6 are shown as mean±standard error ofthe mean; the number of trials conducted for each assay is shown inparentheses except for only a single trial where no number of trials isshown in parentheses. The results in Table 6 demonstrate that manyCompounds of Formulae (I) and/or (II) are potent TRPV1 antagonists.

TABLE 6 TRPV1 IC₅₀ Potency Human Heat Human Capsaicin Human pH CHO CHOCHO (hpH-CHO) (hHeat-CHO) Compound # (hCAP-CHO) (nM) (nM) (nM) StructureA122(a) 177 ± 69  (3) 98 ± 27 (2)

A122(b) 444 ± 79  (3) 670 ± 94  (2)

A122(c) 178 ± 29  (3) 553 ± 12  (2)

A122(e) 80.6 ± 7.5  (3) 5.8 ± 0.7 (2) 96.0 ± 2.4  (2)

A123(e) 11.5 ± 1.4  (3) 0.4 ± 0.0 (2)

A125(b) 112 ± 32  (3) 81 ± 13 (3) 389 ± 83  (3)

A125(e) 23.9 ± 3.8  (3) 0.6 ± 0.2 (2) 18.4 ± 0.8  (2)

A126(a) 40.2 ± 11.0 (4) 12.2 ± 5.9  (2)

A126(e) 18.2 ± 2.9  (3) 0.4 ± 0.0 (3)

A155(a) 96 ± 18 (4) 700 (2)

A155(b) 216 ± 57  (3) 134 ± 16  (4)

A155(d) 168 ± 42  (3)

A155(e) 16.5 ± 4.2  (4)

A158(a) 62.4 ± 13.8 (3) 17.1

B122(j) 586 ± 78  (3) 1723

B122(k) 502 ± 128 (3) 2045 ± 245  (2)

B122(o) 199 ± 38  (3) 6881

B122(p) 506 ± 155 (3) 1016

B125(j) 194 ± 49  (3) 303

B125(k) 186 ± 16  (3) 415

B125(o) 309 ± 105 (3) 398 ± 152 (2)

B125(p) 171 ± 1  (3) 211 ± 50  (2)

B155(h) 107 ± 20  (4)

B155(j) 344 ± 116 (3) 439 ± 71  (2)

B155(o) 249 ± 34  (3) 1233 ± 595  (2)

B158(j) 49 ± 10 (3) 136 ± 20  (3)

B158(o) 146 ± 52  (3) 171 ± 29  (2)

C4(r) 42.8 ± 2.0  (3) 17.4 ± 1.2  (2) 87 ± 13 (2)

C123(r) 26.9 ± 3.6  (3) 20.6 ± 2.6  (4) 96 ± 14 (2)

C125(r) 99 ± 24 (3) 69 ± 3  (2) 335 ± 40  (2)

C126(r) 71 ± 20 (3) 67 ± 12 (2) 155 ± 25 (2)

C170(r) 89 ± 34 (3) 32.8 ± 8.1  (3) 170 ± 20 (2)

AE 68 ± 17 (4) 40.8 ± 3.2  (3) 101.5 ± 0.8  (2)

BB 63.7 ± 13.4 (3) 490

5.16 Example 16 In Vivo Assays for Prevention or Treatment of Pain

Test Animals: Each experiment uses rats weighing between 200-260 g atthe start of the experiment. The rats are group-housed and have freeaccess to food and water at all times, except prior to oraladministration of a Compound of Formula (I) when food is removed for 16hours before dosing. A control group acts as a comparison to ratstreated with a Compound of Formula (I). The control group isadministered the vehicle for the Compound of Formula (I). The volume ofvehicle administered to the control group is the same as the volume ofcarrier and Compound of Formula (I) administered to the test group.

Acute Pain: To assess the actions of a Compound of Formula (I) for thetreatment or prevention of acute pain, the rat tail flick test can beused. Rats are gently restrained by hand and the tail exposed to afocused beam of radiant heat at a point 5 cm from the tip using a tailflick unit (Model 7360, commercially available from Ugo Basile ofItaly). Tail flick latencies are defined as the interval between theonset of the thermal stimulus and the flick of the tail. Animals notresponding within 20 seconds are removed from the tail flick unit andassigned a withdrawal latency of 20 seconds. Tail flick latencies aremeasured immediately before (pre-treatment) and 1, 3, and 5 hoursfollowing administration of a Compound of Formula (I). Data areexpressed as tail flick latency(s) and the percentage of the maximalpossible effect (% MPE), i.e., 20 seconds, is calculated as follows:

${\%\mspace{14mu}{MP}\; E} = {\frac{\begin{bmatrix}{\left( {{post}\text{-}{administration}\mspace{14mu}{latency}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu}{latency}} \right)\end{bmatrix}}{\left( {20\mspace{14mu} s\mspace{11mu}{pre}\text{-}{administration}\mspace{14mu}{latency}} \right)\;} \times 100}$

The rat tail flick test is described in D'Amour et al., “A Method forDetermining Loss of Pain Sensation,” J. Pharmacol. Exp. Ther. 72:74-79(1941).

Inflammatory Pain: To assess the actions of a Compound of Formula (I)for the treatment or prevention of inflammatory pain, the Freund'scomplete adjuvant (“FCA”) model of inflammatory pain was used.FCA-induced inflammation of the rat hind paw is associated with thedevelopment of persistent inflammatory mechanical hyperalgesia andprovides reliable prediction of the anti-hyperalgesic action ofclinically useful analgesic drugs (Bartho et al., “Involvement ofcapsaicin-sensitive neurons in hyperalgesia and enhanced opioidantinociception in inflammation,” Naunyn-Schmiedeberg's Archives ofPharmacol. 342:666-670 (1990)). The right hind paw of each male, 6-weekold Jcl:SD rat was administered a 50 μL intraplantar injection of 50%FCA (Sigma-Aldrich). 24 hour post-injection, the animal was assessed forresponse to noxious mechanical stimuli by determining the PWT, asdescribed below. Rats were then administered a single injection of 0.1,0.3, 1, 3, or 10 mg/kg of either the product prepared with CompoundA155(a) and fumaric acid as described in Example 10, 20 mg/kg of anibuprofen control (EMD Millipore Chemicals, Inc.), or vehicle as acontrol (0.5% weight/volume methylcellulose (400 cP, Wako Pure ChemicalIndustries, Ltd., Osaka, Japan)/aqueous solution). An amount of fumaricacid (AK Scientific) comparable to that present with the productprepared with Compound A155(a) and fumaric acid as described in Example10 was also present in each control. Responses to noxious mechanicalstimuli were then determined 1, 3, 5, and 7 hours post-administration.Percentage reversal of hyperalgesia for each animal was defined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\text{-}{administration}\mspace{14mu}{PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)} \right\rbrack} \times 100}$

With the exception of the controls (i.e., ibuprofen, vehicle) where thestudent's t-test was used, Dunnett's test was conducted for the %reversal. In either instance, values with p<0.05 were considered to bestatistically significant. The % reversal results for administration ofthe product prepared with Compound A155(a) and fumaric acid as describedin Example 10 and the respective controls are presented in Table 7.

TABLE 7 Inflammatory Pain Relief after Administration of the ProductPrepared with Compound A155(a) and Fumaric Acid as Described in Example10 Time after % Reversal [mean] Administration Example 10 ProductComprising Compound A155(a) lbuprofen Vehicle (hours) 0.1 mg/kg 0.3mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 20 mg/kg 2 mL/kg Pre-administration 0 0 00 0 0 0 1 31.9** 65.0** 79.4** 80.3** 102.5** 28.6^(††) −2.0 3 37.8**60.2** 84.1** 87.9** 94.1** 41.5^(††) −2.2 5 31.3** 54.1** 78.2** 86.6**97.3** 39.2^(††) 2.3 7 23.6** 39.4** 70.5** 97.3** 93.1** 32.5^(††) 1.1**indicates p < 0.01 (Dunnett's test), ^(††)indicates p < 0.01(student's t-test).

As demonstrated by the results in Table 7, assessments of the actions ofthe Compounds of Formula (I) revealed that these compounds wereefficacious, e.g., the product prepared with Compound A155(a) andfumaric acid as described in Example 10 significantly reducedFCA-induced inflammation, with ED₅₀ values of from about 0.2 mg/kg toabout 0.4 mg/kg and maximum % reversal values of from about 24% to about100%. For example, the % reversal of FCA-induced inflammation afteradministration of a 3 mg/kg dose of the product prepared with CompoundA155(a) and fumaric acid as described in Example 10 was about 80% orabove, i.e., 80.3% at 1 hour after administration, 87.9% at 3 hoursafter administration, 86.6% at 5 hours after administration, and 97.3%at 7 hours after administration of the product prepared with CompoundA155(a) and fumaric acid as described in Example 10.

Even at the minimal effective dose of 0.1 mg/kg of the product preparedwith Compound A155(a) and fumaric acid as described in Example 10, the %reversal of FCA-induced inflammation was about 24% or above, i.e., 31.9%at 1 hour after administration, 37.8% at 3 hours after administration,31.3% at 5 hours after administration, and 23.6% at 7 hours afteradministration of the product prepared with Compound A155(a) and fumaricacid as described in Example 10. In contrast, a 20 mg/kg dose ofibuprofen was far less effective than a 0.3 mg/kg dose of the productprepared with Compound A155(a) and fumaric acid as described in Example10 at each time-point tested, i.e., 28.6% versus 65.0% respectively at 1hour after administration, 41.5% versus 60.2% respectively at 3 hoursafter administration, 39.2% versus 54.1% respectively at 5 hours afteradministration, and 32.5% versus 39.4% respectively at 7 hours afteradministration. In making this comparison, it should be noted that thedose of ibuprofen administered, 20 mg/kg, was over 66 times greater thanthe dose of the product prepared with Compound A155(a) and fumaric acidas described in Example 10, 0.3 mg/kg.

Osteoarthritis Pain: To assess the actions of a Compound of Formula (I)for the treatment or prevention of osteoarthritis pain, the ratmonosodium iodo-acetate (MIA, i.e., sodium 2-iodoacetate) inducedosteoarthritis model was used. Intra-articular injection of MIA causesjoint degeneration characterized by osteolysis and swelling, withdisplacement of the patella, and reductions in bone mineral content andbone mineral density (Pomonis et al., “Development and pharmacologicalcharacterization of a rat model of osteoarthritis pain,” Pain 114:339-346 (2005)). Under isoflurane anaesthesia, an intra-articularinjection of 2 mg of MIA (Sigma-Aldrich) in 50 μl of saline wasadministered through the infrapatellar ligament of the knee joint of theright hind leg of the male, 6 week old Crl:CD(SD) rats. Control ratsreceived an intra-articular injection of 50 μl of saline into the kneejoint of the right hind leg. The left knee joint of all rats wasuntreated. Two weeks after MIA injection, rats were assessed forosteoarthritis pain related-behaviors immediately prior to and 1, 3, 5,7, and 24 hours after oral drug-in-vehicle administration (for day 1) bydetermining their weight-bearing capabilities, via the weight bearingdifference (WBD) test, and their gripping capabilities, via the gripforce test, each as described below. Thus, in the assessment forosteoarthritis pain relief through gripping capability determinations,the 24 hour time point was the start of the next day whendrug-in-vehicle was again orally administered (24 hours after the prioradministration) for certain dosages. On days 2, 3, and 4, grippingcapability response was determined 3 and 24 hours thereafter.

Additionally, 3 mg/kg of celecoxib (BioVision Inc., Milpitas, Calif.), ahighly selective COX-2 inhibitor accepted for relief of inflammation andpain, in vehicle and the vehicle alone (0.5% weight/volumemethylcellulose (400 cP, Wako Pure Chemical Industries, Ltd.)/aqueoussolution) were orally administered as controls. An amount of fumaricacid comparable to that present with the product prepared with CompoundA155(a) and fumaric acid as described in Example 10 was also present ineach control.

Weight Bearing Difference Test as an Assessment of OsteoarthritisRelated Pain: The weight bearing difference test provides an acceptedassessment of the efficacy of clinically useful analgesic drugs withrespect of osteoarthritis related pain (see Pomonis et al. (2005)). WBDwas assessed using a Linton Incapacitance Tester (LintonInstrumentation, Norfolk, UK). Rats were placed on the apparatus so thatthey were standing on their hind legs, and allowed to acclimate to theapparatus. When stationary, the weight born on each leg was measuredover a 3 s period. Three readings were taken for each rat at each timepoint; the average of the three readings was used for data analysis. WBDwas expressed as “% WR”, i.e., the percentage of weight born on theMIA-injected right hind leg, using the following formula:

${\%\mspace{11mu}{WR}} = {\frac{WR}{\left( {{WR} + {WL}} \right)} \times 100}$where WR is the weight on the right hind leg and WL is the weight on theleft (untreated) hind leg. The 50% value of % WR corresponds to an equalweight distribution across both hind legs. The “% WRR”, i.e., thepercentage reversal of the % WR impediment occurring post-MIA injection,was determined for each dosage at each time point using the followingformula:

${\%\mspace{14mu}{WRR}} = {\frac{\left\lbrack {\left( {\%\mspace{14mu}{WR}} \right)_{{Post}\text{-}{Drug}} - \left( {\%\mspace{14mu}{WR}} \right)_{{Pre}\text{-}{Drug}}} \right\rbrack}{\left\lbrack {\left( {\%\mspace{14mu}{WR}} \right)_{{Control}\mspace{14mu}{Rat}} - \left( {\%\mspace{14mu}{WR}} \right)_{{Pre}\text{-}{Drug}}} \right\rbrack} \times 100}$where (% WR)Post-Drug is the % WR determined at eachpost-oral-administration time-point for each dose of each administeredsubstance, (% WR)_(Pre-Drug) is the % WR determinedpre-oral-administration of each administered substance, and (%WR)_(Control Rat) is the % WR determined for control rats (receiving thesaline injection into the right hind leg knee joint). With the exceptionof the controls (i.e., celecoxib, vehicle) where the student's t-testwas used, Dunnett's test was conducted for the % WRR. In eitherinstance, values with p<0.05 were considered to be statisticallysignificant. The % WRR results for administration of the productprepared with Compound A155(a) and fumaric acid as described in Example10 are presented in Table 8.

TABLE 8 Osteoarthritis Pain Relief after Administration of the ProductPrepared with Compound A155(a) and Fumaric Acid as Described in Example10 as Assessed by the Weight Bearing Difference Test Time after % WRR[mean] Administration Example 10 Product Comprising Compound A155(a)Celecoxib Vehicle (hours) 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 20 mg/kg 3mg/kg 2 mL/kg Pre-administration 0 0 0 0 0 0 0 1 4.3 15.2 20.9** 33.3**41.9** 10.2^(†) 3.4 3 12.5 28.8** 34.5** 44.1** 56.9** 27.8^(††) −0.2 57.1 16.1** 23.4** 35.0** 46.9** 14.1^(††) −2.7 7 5.0 8.8* 9.5* 22.8**35.6** 6.0^(†) −4.4 24 0 2.1 3.7 9.8 19.8** 2.0 −1.2 *indicates p < 0.05(Dunnett's test), **indicates p < 0.01 (Dunnett's test), ^(†)indicates p< 0.05 (student's t-test), ^(††)indicates p < 0.01 (student's t-test).

As demonstrated by the results in Table 8, assessments of the actions ofthe Compounds of Formula (I) revealed that these compounds wereefficacious, e.g., the product prepared with Compound A155(a) andfumaric acid as described in Example 10 significantly reducedosteoarthritis pain, as determined by WBD, with maximum % reversalvalues of from about 8.8% to about 56.9%. For example, the % reversal ofosteoarthritis pain after administration of a 20 mg/kg dose of theproduct prepared with Compound A155(a) and fumaric acid as described inExample 10 was about 20% or above, i.e., 41.9% at 1 hour afteradministration, 56.9% at 3 hours after administration, 46.9% at 5 hoursafter administration, 35.6% at 7 hours after administration, and even19.8% at 24 hours after administration of the product prepared withCompound A155(a) and fumaric acid as described in Example 10.

Even at the minimal effective dose of 1 mg/kg of the product preparedwith Compound A155(a) and fumaric acid as described in Example 10, the %WR was about 9% or above, i.e., 15.2% at 1 hour after administration,28.8% at 3 hours after administration, 16.1% at 5 hours afteradministration, and 8.8% at 7 hours after administration of the productprepared with Compound A155(a) and fumaric acid as described in Example10. In contrast, a 3 mg/kg dose of celecoxib was less effective than a 1mg/kg dose of the product prepared with Compound A155(a) and fumaricacid as described in Example 10 at each less-than-24 hour time-pointtested, i.e., 10.2% versus 15.2% respectively at 1 hour afteradministration, 27.8% versus 28.8% respectively at 3 hours afteradministration, 14.1% versus 16.1% respectively at 5 hours afteradministration, and 6.0% versus 8.8% respectively at 7 hours afteradministration. In making this comparison, it should be noted that thedose of celecoxib administered, 3 mg/kg, was 3 times greater than thedose of the product prepared with Compound A155(a) and fumaric acid asdescribed in Example 10, 1 mg/kg.

Grip Force Test as an Assessment of Osteoarthritis Related Pain: Thegrip force test provides an accepted assessment of the efficacy ofclinically useful analgesic drugs with respect of osteoarthritis relatedpain (Chandran et al., “Pharmacological modulation of movement-evokedpain in a rat model of osteoarthritis,” Eur. J. Pharmacol. 613:39-45(2009); Chu et al., “TRPV1-related modulation of spinal neuronalactivity and behavior in a rat model of osteoarthritic pain,” Brain Res.1369:158-166 (2011)). The grip force (GF) of the hind legs was assessedusing a Animal Grip Strength System (San Diego Instruments, San Diego,Calif.). Rats were gently restrained and allowed to grasp the wire meshstrain gauge with their hind legs. The animals were then moved in arostral-caudal direction until they let go of the gauge. The force (ing) at which the rat let go was recorded. Each animal was tested twice atapproximately 3-10 minute intervals at each time point and the averageof the two readings was used for the GF in data analysis.

Grip force, normalized to account for the weight of each animal, wasexpressed as “GF/B”, i.e., the ratio of GF to body weight, where GF isthe grip force in grams and B is the body weight of the animal in kg.The “% GFR”, i.e., the percentage reversal of the (normalized) gripforce impediment occurring post-MIA injection, was determined for eachdosage at each time point using the following formula:

${\%\mspace{14mu}{GFR}} = {\frac{\left\lbrack {{\left( {{GF}\text{/}B} \right){Drug}} - {\left( {{GF}\text{/}B} \right){Vehicle}}} \right\rbrack}{\left\lbrack {\left( {{GF}\text{/}B} \right)_{{Control}\mspace{14mu}{Rat}} - \left( {{GF}\text{/}B} \right)_{Vehicle}} \right\rbrack} \times 100}$where (GF/B)_(Drug) is the GF/B determined at eachpost-oral-administration time-point for each dose of each substanceadministered to MIA-injected animals, (GF/B)_(Vehicle) is the GF/Bdetermined at each post-oral-administration time-point for the vehiclecontrol administered to MIA-injected animals, and (GF/B)_(Control Rat)is the GF/B determined for control rats (saline-injected animalsreceiving orally-administered vehicle only). With the exception of thecontrols (i.e., celecoxib, vehicle) where the student's t-test was used,Dunnett's test was conducted for the % GFR. In either instance, valueswith p <0.05 were considered to be statistically significant. The % GFRresults for administration of the product prepared with Compound A155(a)and fumaric acid as described in Example 10 are presented in Table 9.

TABLE 9 Osteoarthritis Pain Relief after Administration of the ProductPrepared with Compound A155(a) and Fumaric Acid as Described in Example10 as Assessed by the Grip Force Test Time after % GFR [mean]Administration Example 10 Product Comprising Compound A155(a) CelecoxibVehicle (hours) 0.3 mg/kg 1 mg/kg 3 mg/kg 10 mg/kg 20 mg/kg 3 mg/kg 2mL/kg Pre-administration 2.2 1.0 0 −2.6 2.3 −3.7 0 1 (day 1) 12.8 29.7**36.5** 35.9** 49.0** 22.6^(††) 1.2 3 (day 1) 21.1* 45.2** 53.6** 55.6**65.1** 30.0^(††) 2.4 5 (day 1) 17.3* 37.6** 44.3** 45.9** 50.3**20.9^(††) 0.8 7 (day 1) 3.7 16.5* 19.9** 22.8** 29.3** 3.6 −2.1 24 (0hrs day 2) 4.0 3.1 −2.2 −5.7 −1.3 −3.6 −4.3 3 (day 2) 43.1** 50.5**57.5** 2.9 24 (0 hrs day 3) 15.4** 22.0** 32.7** −4.7 3 (day 3) 38.0**45.0** 51.6** −0.7 24 (0 hrs day 4) 26.1** 32.0** 33.4** −5.4 3 (day 4)40.1** 45.6** 52.2** −5.5 24 (0 hrs day 5) 26.4** 28.9** 32.0** −5.7*indicates p < 0.05 (Dunnett's test), **indicates p < 0.01 (Dunnett'stest), ^(††)indicates p < 0.01 (student's t-test).

As demonstrated by the results in Table 9, one-time administration ofthe product prepared with Compound A155(a) and fumaric acid as describedin Example 10 (0.3, 1, 3, 10, or 20 mg/kg) and once daily administrationof the product prepared with Compound A155(a) and fumaric acid asdescribed in Example 10 (1, 3, or 10 mg/kg) for four days showedstatistically significant effects against MIA-induced osteoarthritispain in rats. Following a single administration, the maximum analgesiceffect of the product prepared with Compound A155(a) and fumaric acid asdescribed in Example 10 at 1 and 3 mg/kg (and 10 and 20 mg/kg) wasgreater than the effect of celecoxib at 3 mg/kg. Thus, Compounds ofFormula (I) are effective in relieving osteoarthritis pain in vivo.

In particular, a single administration of the product prepared withCompound A155(a) and fumaric acid as described in Example 10demonstrated analgesic effects in the MIA-induced osteoarthritis painmodel. Following dosing at 20 mg/kg, the product prepared with CompoundA155(a) and fumaric acid as described in Example 10 evidencedsignificant analgesic effects at 1, 3, 5, and 7 hourspost-administration. The maximum analgesic efficacy observed with theproduct prepared with Compound A155(a) and fumaric acid as described inExample 10 was 65.1% reversal achieved 3 hours after administration.Similarly, following dosing at 1, 3, and 10 mg/kg, the product preparedwith Compound A155(a) and fumaric acid as described in Example 10evidenced significant analgesic effects at 1, 3, 5, and 7 hours afteradministration. Further, even following dosing at 0.3 mg/kg, the productprepared with Compound A155(a) and fumaric acid as described in Example10 evidenced significant analgesic effects at 3 and 5 hours afteradministration. The maximum analgesic efficacy at 0.3, 1, 3, and 10mg/kg of the product prepared with Compound A155(a) and fumaric acid asdescribed in Example 10 was 21.1%, 45.2%, 53.6%, and 55.6% reversal,respectively, each at 3 hours post-administration. These resultsdemonstrate that a dose-dependent significant analgesic effect wasachieved.

The results of repeated administration for 4 days of the productprepared with Compound A155(a) and fumaric acid as described in Example10 also demonstrate a dose-dependent significant analgesic effect. Onday 2 of dosing, the product prepared with Compound A155(a) and fumaricacid as described in Example 10 demonstrated a dose-dependentsignificant analgesic effect at 3 hours after administration. Theanalgesic efficacy following dosing at 1, 3, and 10 mg/kg of the productprepared with Compound A155(a) and fumaric acid as described in Example10 was 43.1%, 50.5%, and 57.5% reversal, respectively. On day 3 ofdosing, 1, 3, and 10 mg/kg of the product prepared with Compound A155(a)and fumaric acid as described in Example 10 demonstrated dose-dependentsignificant analgesic effects with 38.0%, 45.0%, and 51.6% reversal,respectively. On day 4 of dosing, 1, 3, and 10 mg/kg of the productprepared with Compound A155(a) and fumaric acid as described in Example10 demonstrated dose-dependent significant analgesic effects with 40.1%,45.6%, and 52.2% reversal, respectively.

Moreover, these results demonstrate that there is, desirably, a lack oftolerance development with repeated administration. For example, dosingat 10 mg/kg of the product prepared with Compound A155(a) and fumaricacid as described in Example 10 evidenced roughly comparable maximumanalgesic efficacy 3 hours after each administration, 55.6%, 57.5%,51.6%, and 52.2% reversal, respectively, after day 1, 2, 3, and 4administration.

Oral single dosing of celecoxib, the positive control, also producedanalgesic effects in the MIA-induced osteoarthritis pain model.Following dosing at 3 mg/kg, celecoxib showed significant analgesiceffects at 1, 3, and 5 hours post-administration. However, the maximumanalgesic efficacy observed with celecoxib, 30.0% reversal 3 hours afterday 1 administration of the 3 mg/kg dose, was only about 66.4% and56.0%, respectively, of the 45.2% reversal at 1 mg/kg (i.e., one thirdthe celecoxib dose) and 53.6% reversal at 3 mg/kg, each achieved 3 hoursafter day 1 administration of the product prepared with Compound A155(a)and fumaric acid as described in Example 10.

Neuropathic Pain: To assess the actions of a Compound of Formula (I) forthe treatment or prevention of neuropathic pain, either the Seltzermodel or the Chung model can be used.

In the Seltzer model, the partial sciatic nerve ligation model ofneuropathic pain was used to produce neuropathic hyperalgesia in rats(Seltzer et al., “A Novel Behavioral Model of Neuropathic Pain DisordersProduced in Rats by Partial Sciatic Nerve Injury,” Pain 43:205-218(1990)). Partial ligation of the left sciatic nerve was performed underisoflurane/O₂ inhalation anaesthesia. Following induction of anesthesia,the left thigh of the male, 6-7 week old Jcl:SD rat was shaved. Thesciatic nerve was exposed at high thigh level through a small incisionand was carefully cleared of surrounding connective tissues at a sitenear the trocanther just distal to the point at which the posteriorbiceps semitendinosus nerve branches off of the common sciatic nerve. A7-0 silk suture was inserted into the nerve with a ⅜ curved,reversed-cutting mini-needle and tightly ligated so that the dorsal ⅓ to½ of the nerve thickness was held within the ligature. The wound wasclosed with a single muscle suture (4-0 nylon (Vicryl)) and vetbondtissue glue. The wound area was then dusted with antibiotic powder. Shamtreatment involved an identical surgical procedure except that thesciatic nerve was not manipulated or ligated.

Following surgery, animals were weighed and placed on a warm pad untilthey recovered from anesthesia. Animals were then returned to their homecages until behavioral testing began. The animal was assessed forresponse to noxious mechanical stimuli by determining PWT for the rearpaw of the animal, as described below, prior to surgery (baseline), thenimmediately prior to and 1, 3, 5, 7, and 24 hours after oraldrug-in-vehicle administration (for day 1). Thus, the 24 hour time pointwas the start of the next day when drug-in-vehicle was again orallyadministered (24 hours after the prior administration). On days 2 and 3,PWT response was determined 1, 3, and 24 hours thereafter. Percentagereversal of neuropathic hyperalgesia at each of the specified timesafter administration was defined as:

${\%\mspace{14mu}{Reversal}} = {\frac{\begin{bmatrix}{\left( {{post}\text{-}{administration}\mspace{14mu}{PWT}} \right) -} \\\left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)\end{bmatrix}}{\left\lbrack {\left( {{baseline}\mspace{14mu}{PWT}} \right) - \left( {{pre}\text{-}{administration}\mspace{14mu}{PWT}} \right)} \right\rbrack} \times 100}$

Additionally, 10 mg/kg of pregabalin (Kemprotec, Ltd., Middlesbrough,UK), an anticonvulsant accepted for relief of particular neuropathicpain, in vehicle and the vehicle alone (0.5% weight/volumemethylcellulose (400 cP, Wako Pure Chemical Industries, Ltd.)/aqueoussolution) were orally administered as controls. An amount of fumaricacid comparable to that present with Compound A155(a) was also presentin each control. Ten rats that underwent partial ligation of the leftsciatic nerve were used for each treatment group. Dunnett's test wasconducted for the % reversal; values with p<0.05 were considered to bestatistically significant. The results for administration of the productprepared with Compound A155(a) and fumaric acid as described in Example10 are provided in Table 10.

TABLE 10 Neuropathic Pain Relief after Administration of the ProductPrepared with Compound A155(a) and Fumaric Acid as Described in Example10 Time after % Reversal [mean ± SEM] Administration Example 10 ProductComprising Compound A155(a) Pregabalin Vehicle (hours) 1 mg/kg 3 mg/kg10 mg/kg 10 mg/kg 2 mL/kg Pre-administration 0 0 0 0 0 1 (day 1) 14.60 ±4.26  15.69 ± 4.62  32.51 ± 5.00** 24.05 ± 6.46** −0.75 ± 1.50 3 (day 1) 17.04 ± 4.91**  18.39 ± 1.67** 34.17 ± 5.60** 24.73 ± 4.12** −4.39 ±1.80 5 (day 1) 11.39 ± 3.13*  12.22 ± 1.89** 19.59 ± 3.04** 19.97 ±4.79** −2.98 ± 2.54 7 (day 1) 3.04 ± 4.49 7.65 ± 2.79 17.06 ± 2.95**11.89 ± 3.16** −3.64 ± 2.99 24 (0 hrs day 2) 0.71 ± 2.46 −5.34 ± 4.20 3.38 ± 3.97  −2.84 ± 4.74  −6.84 ± 3.04 1 (day 2) 12.04 ± 4.92* 12.57 ±2.38* 27.41 ± 4.56** 16.74 ± 4.23** −3.82 ± 1.90 3 (day 2) 12.84 ± 4.12* 17.14 ± 5.38** 29.12 ± 5.44** 23.21 ± 2.30** −4.81 ± 1.61 24 (0 hrs day3) 4.89 ± 2.68 −3.85 ± 4.61  2.87 ± 4.62  1.70 ± 4.29  −0.58 ± 4.19 1(day 3) 6.44 ± 6.50 11.80 ± 3.29  23.36 ± 4.69** 17.16 ± 6.64*  −2.20 ±2.37 3 (day 3) 9.58 ± 5.23 17.34 ± 3.91* 28.91 ± 5.72** 26.56 ± 4.95** 1.32 ± 2.14 24 (0 hrs day 4) 0.51 ± 3.15 −1.95 ± 2.97  11.09 ± 3.45 −3.67 ± 2.66   1.02 ± 2.19 *indicates p < 0.05 (Dunnett's test),**indicates p < 0.01 (Dunnett's test).

Additionally, as a control the rats underwent sham surgery in which anidentical surgical procedure was followed with regard to the right thighbut the sciatic nerve was neither manipulated nor ligated.

As demonstrated by the results in Table 10, once daily administration ofthe product prepared with Compound A155(a) and fumaric acid as describedin Example 10 (1, 3, or 10 mg/kg) for three days showed statisticallysignificant effects against mechanical hyperalgesia in rats subjected topartial sciatic nerve ligation in the Seltzer model of neuropathic pain.Following either a single administration or repeated administration for3 days, the maximum analgesic effect of the product prepared withCompound A155(a) and fumaric acid as described in Example 10 at 10 mg/kgwas greater than the effect of pregabalin at 10 mg/kg. Thus, Compoundsof Formula (I) are effective in relieving neuropathic pain in vivo.

In particular, a single administration of the product prepared withCompound A155(a) and fumaric acid as described in Example 10demonstrated analgesic effects in the Selzer model. Following dosing at10 mg/kg, the product prepared with Compound A155(a) and fumaric acid asdescribed in Example 10 evidenced significant analgesic effects at 1, 3,5, and 7 hours post-administration. The maximum analgesic efficacyobserved with the product prepared with Compound A155(a) and fumaricacid as described in Example 10 was 34.17% reversal achieved 3 hoursafter administration. Similarly, following dosing at 1 and 3 mg/kg, theproduct prepared with Compound A155(a) and fumaric acid as described inExample 10 evidenced significant analgesic effects at 3 and 5 hoursafter administration. The maximum analgesic efficacy at 1 and 3 mg/kg ofthe product prepared with Compound A155(a) and fumaric acid as describedin Example 10 was 17.04% and 18.39% reversal, respectively. Theseresults demonstrate that a dose-dependent significant analgesic effectwas achieved.

The results of repeated administration for 3 days of the productprepared with Compound A155(a) and fumaric acid as described in Example10 also demonstrate a dose-dependent significant analgesic effect. Onday 2 of dosing, the product prepared with Compound A155(a) and fumaricacid as described in Example 10 demonstrated a dose-dependentsignificant analgesic effect at 1 and 3 hours after administration. Themaximum analgesic efficacy following dosing at 1, 3, and 10 mg/kg of theproduct prepared with Compound A155(a) and fumaric acid as described inExample 10 was 12.84%, 17.14%, and 29.12% reversal, respectively, eachat the 3 hour time point. On day 3 of dosing, 3 and 10 mg/kg of theproduct prepared with Compound A155(a) and fumaric acid as described inExample 10 demonstrated dose-dependent significant analgesic effectswith maxima of 17.34% reversal at 3 mg/kg and 28.91% reversal at 10mg/kg, each at the 3 hour time point.

Moreover, these results demonstrate that there is, desirably, a lack oftolerance development with repeated administration. For example, dosingat 3 mg/kg of the product prepared with Compound A155(a) and fumaricacid as described in Example 10 evidenced roughly comparable maximumanalgesic efficacy 3 hours after each administration, 18.39%, 17.14%,and 17.34% reversal, respectively, after day 1, 2, and 3 administration.

Oral single dosing of pregabalin, the positive control, also producedanalgesic effects in the Selzer model. Following dosing at 10 mg/kg,pregabalin showed significant analgesic effects at 1, 3, 5, and 7 hourspost-administration. However, the maximum analgesic efficacy observedwith pregabalin, 24.73% reversal 3 hours after day 1 administration ofthe 10 mg/kg dose, was only about 72% of the 34.17% reversal achieved 3hours after day 1 administration of the 10 mg/kg dose of the productprepared with Compound A155(a) and fumaric acid as described in Example10.

In the Chung model, the spinal nerve ligation model of neuropathic painis used to produce mechanical hyperalgesia, thermal hyperalgesia andtactile allodynia in rats. Surgery is performed under isoflurane/O₂inhalation anaesthesia. Following induction of anaesthesia, a 3 cmincision is made and the left paraspinal muscles are separated from thespinous process at the L₄-S₂ levels. The L₆ transverse process iscarefully removed with a pair of small rongeurs to identify visually theL₄-L₆ spinal nerves. The left L₅ (or L₅ and L₆) spinal nerve(s) isisolated and tightly ligated with silk thread. A complete hemostasis isconfirmed and the wound is sutured using non-absorbable sutures, such asnylon sutures or stainless steel staples. Sham-treated rats undergo anidentical surgical procedure except that the spinal nerve(s) is notmanipulated. Following surgery animals are weighed, administered asubcutaneous (s.c.) injection of saline or ringers lactate, the woundarea is dusted with antibiotic powder and they are kept on a warm paduntil they recover from the anesthesia. Animals are then returned totheir home cages until behavioral testing begins. The animals areassessed for response to noxious mechanical stimuli by determining PWT,as described below, prior to surgery (baseline), then immediately priorto and 1, 3, and 5 hours after being administered a Compound of Formula(I) for the left rear paw of the animal. The animal can also be assessedfor response to noxious thermal stimuli or for tactile allodynia, asdescribed below. The Chung model for neuropathic pain is described inKim, “An Experimental Model for Peripheral Neuropathy Produced bySegmental Spinal Nerve Ligation in the Rat,” Pain 50(3):355-363 (1992).

Response to Mechanical Stimuli as an Assessment of MechanicalHyperalgesia: The paw pressure assay was used to assess mechanicalhyperalgesia. For this assay, hind paw withdrawal thresholds (PWT) to anoxious mechanical stimulus were determined using an analgesymeter(Model 37215, commercially available from Ugo Basile of Italy) asdescribed in Stein, “Unilateral Inflammation of the Hindpaw in Rats as aModel of Prolonged Noxious Stimulation: Alterations in Behavior andNociceptive Thresholds,” Pharmacol. Biochem. and Behavior 31:451-455(1988). The maximum weight that could be applied to the hind paw was setat 250 g and the end point was taken as complete withdrawal of the paw.PWT was determined once for each rat at each time point and either onlythe affected (ipsilateral) paw was tested, or both the ipsilateral andcontralateral (non-injured) paw were tested.

Response to Thermal Stimuli as an Assessment of Thermal Hyperalgesia:The plantar test can be used to assess thermal hyperalgesia. For thistest, hind paw withdrawal latencies to a noxious thermal stimulus aredetermined using a plantar test apparatus (commercially available fromUgo Basile of Italy) following the technique described by Hargreaves etal., “A New and Sensitive Method for Measuring Thermal Nociception inCutaneous Hyperalgesia,” Pain 32(1):77-88 (1988). The maximum exposuretime is set at 32 seconds to avoid tissue damage and any directed pawwithdrawal from the heat source is taken as the end point. Threelatencies are determined at each time point and averaged. Either onlythe affected (ipsilateral) paw is tested, or both the ipsilateral andcontralateral (non-injured) paw are tested.

Assessment of Tactile Allodynia: To assess tactile allodynia, rats areplaced in clear, plexiglass compartments with a wire mesh floor andallowed to habituate for a period of at least 15 minutes. Afterhabituation, a series of von Frey monofilaments are presented to theplantar surface of the left (operated) foot of each rat. The series ofvon Frey monofilaments consists of six monofilaments of increasingdiameter, with the smallest diameter fiber presented first. Five trialsare conducted with each filament with each trial separated byapproximately 2 minutes. Each presentation lasts for a period of 4-8seconds or until a nociceptive withdrawal behavior is observed.Flinching, paw withdrawal or licking of the paw are considerednociceptive behavioral responses.

Capsaicin-Induced Eye Wipe Test: To assess the effect of Compounds ofFormula (I) on TRPV1 receptor-mediated pain, the capsaicin-induced eyewipe test is used (Gavva et al., “AMG 9810[(E)-3-(4-t-Butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide],a Novel Vanilloid Receptor 1 (TRPV1) Antagonist with AntihyperalgesicProperties”, J. Pharmacol. Exp. Ther. 313:474-484 (2005)). The eye wipetest is a reliable high-throughput test of the effect of TRPV1antagonists. Rats are given a single injection of 1, 3, 10, or 30 mg/kgof either a Compound of Formula (1), 30 mg/kg of a control selected fromCelebrex, indomethacin, ibuprofen, or naproxen, or a vehicle. At 1, 3,or 5 hours after drug administration, 3 μL of a 100 μM capsaicinsolution (in 10% EtOH/PBS) is instilled in one eye of each animal with apipette. The number of forelimb movements (touching or wiping of thecapsaicin-treated eye) are counted during a 2 minute period followinginstillation of capsaicin into the eye.

5.17 Example 17 In Vivo Assay of Body Temperature Increase

Hyperthermia or undesirable elevation in animal body temperature isknown to be an undesirable side-effect accompanying the administrationof certain TRPV1 antagonists (Gavva, “Body-temperature maintenance asthe predominant function of the vanilloid receptor TRPV1,” TrendsPharmacol. Sci. 29(11):550-557 (2008)). Compounds of Formulae (I) and/or(II) are capable of ameliorating the undesirable side effect ofincreased body temperature that can occur upon in vivo administration,as demonstrated in this example.

Test Animals: Selection of rats (Crl/SD rats, 7 weeks, male) was basedon rectal body temperature measured during the morning of the day ofdosing as described below. In addition, to minimize spontaneous,stress-induced increases in body temperature, rats were acclimated inadvance to both the rectal measurement procedure and to being handledand dosed. All lodging and testing took place in animal carelaboratories with constant room temperature and humidity. The rats werefree to move and ingest food and water throughout. Each rat was codedwith a colored line on the tail, housed in a separate cage, andpermitted the normal range of movement. Immediately before each bodytemperature measurement, a rat was transferred to a measurement cage. Toreduce stress which could influence its body temperature, each rat wascovered with towels during the measurement. A thermistor probe was thencarefully inserted into the rectum of each rat and left in place untilthe temperature reading on the digital display had stabilized; thisvalue was recorded.

Assay: On the day before dosing, rectal body temperature was measured at9:00, 10:00, 11:00, 12:30, 13:30, 14:30, and 15:30 o'clock tofamiliarize the rats with the measurement procedure prior toadministration of the test or control treatments. The rats were alsodosed by oral gavage without vehicle at 12:30 o'clock to acclimate andfamiliarize them with the handling and dosing procedure.

On the day of dosing, only rats with rectal body temperatures within therange of from 37.0° C. to 37.7° C. were selected for study. Rectal bodytemperatures were measured at 9:00, 10:00, and 11:00 o'clock. Rats wereexcluded from the study if either their rectal body temperature was over37.9° C. at 10:00 o'clock or was outside the range of from 37.0° C. to37.7° C. at 11:00 o'clock. The selected rats were divided into severalgroups based on their rectal body temperatures at 11:00 o'clock. Rectalbody temperatures of the selected rats were measured again at 12:30o'clock and any rat with a rectal body temperature of 38.0° C. orgreater was also excluded from the study.

Following assignment to either a test or control group, a test compoundor a control was administered to the rats. Each test compound wasdissolved in a vehicle of 0.5% aqueous methylcellulose solution and thefinal concentration of the test compound was adjusted to 1 mg/mL. Eachtest compound was orally administered once at a dose of 10 mL/kg. Thesame volume of the control (vehicle only) was administered once to thecontrol group. Rectal body temperatures were measured at the followingtime points: 0.5, 1, and 2 hrs after administration.

The body temperature increase (ΔTb) for each test compound wascalculated by subtracting, at each time point, the average temperatureof the control group from the average temperature of the groupadministered that test compound. The greatest ATb obtained for each testcompound at any of the time points is shown in Table 11 below, alongwith the ATb of the control.

TABLE 11 Body Temperature Increase Compound ΔTb (° C.) Structure Control0.0 — A122(a) 0.4 A125(b) 0.1 A126(a) 0.2 A155(a) 0.2 A155(d) 0.1A155(e) 0.1 A158(a) 0.4 B158(j) 0.1 C4(r) 0.3 C125(r) 0.3 C126(r) 0.4C170(r) 0.2 AA 0.8

AB 0.6

AC 0.7

AD 0.6

AE 0.5

BA 0.9

BB 0.5

BC 0.7

DA 0.9

DB 1.1

DC 1.0

DD 1.0

DE 1.3

DF 0.5

DG 1.0

DH 0.9

DI 0.8

DJ 0.9

DK 0.7

DL 0.9

DM 0.9

DN 0.8

DO 1.1

DP 1.2

As demonstrated by the data above, Compounds of Formulae (I) and/or (II)are capable of ameliorating the undesirable side effect of an increasein body temperature that can occur upon in vivo administration of acompound which modulates the TRPV1 receptor. For example, the bodytemperature increase after administration of Compounds of Formulae (I)and/or (II) is less than 0.7° C. in one embodiment, 0.6° C. or less inanother embodiment, less than 0.6° C. in another embodiment, 0.5° C. orless in another embodiment, less than 0.5° C. in another embodiment,0.4° C. or less in another embodiment, less than 0.4° C. in anotherembodiment, 0.3° C. or less in another embodiment, less than 0.3° C. inanother embodiment, or 0.2° C. or less in another embodiment.

In particular, the body temperature increase after administration ofCompounds of Formulae (I) and/or (II) was determined to be less than0.5° C., in some cases much less than 0.5° C., e.g., 0.1° C. forCompounds A125(b), A155(d), A155(e), and B158(j); 0.2° C. for CompoundsA126(a), A155(a), and C170(r); and 0.3° C. for Compounds C4(r) andC125(r). In addition, Compounds of Formulae (I) and/or (II), e.g.,Compound A155(a), showed a significant separation between doseseffective in pain models and doses at which an increase in bodytemperature was observed in both rats and monkeys. Doses that increasedbody temperature were more than 100 times greater than the ED₈₀ in theFCA model of inflammatory pain some instances.

In contrast, the body temperature increase after administration of othercompounds was determined to be greater than 0.5° C., in some cases muchgreater than 0.5° C., e.g., 0.8° C. for Compounds DI, DN, and AA; 0.9°C. for Compounds DA, DH, DJ, DL, DM, and BA; 1.0° C. for Compounds DC,DD, and DG; 1.1° C. for Compounds DB and DO; 1.2° C. for Compound DP;and 1.3° C. for Compound DE; in some instances, these compounds inducedhyperthermia at doses that were less than those necessary for efficacyin pain models, showing a lack of separation between efficacy and theside effect of hyperthermia.

The invention is not to be limited in scope by the specific embodimentsdisclosed in the examples that are intended as illustrations of a fewaspects of the invention and any embodiments that are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the scope of the appended claims. A number of referenceshave been cited, the entire disclosures of which are incorporated hereinby reference for all purposes.

What is claimed:
 1. A co-crystal of (a) a compound which is

and (b) fumaric acid, wherein said co-crystal is characterized by aCP/MAS ¹³C NMR spectrum comprising peaks with a chemical shift of171.5±0.2 ppm, 170.3±0.2 ppm, and 135.6±0.2 ppm when measured by theCP/MAS¹³C NMR procedure described in Example
 10. 2. The co-crystal ofclaim 1, wherein said co-crystal is characterized by a CP/MAS ¹³C NMRspectrum further comprising a peak with a chemical shift of 72.2±0.2 ppmwhen measured by the CP/MAS ¹³C NMR procedure described in Example 10.3. The co-crystal of claim 1, wherein said co-crystal is characterizedby a CP/MAS ¹³C NMR spectrum further comprising peaks with a chemicalshift of 72.2±0.2 ppm and 15.1±0.2 ppm when measured by the CP/MAS ¹³CNMR procedure described in Example
 10. 4. The co-crystal of claim 1,wherein the molar ratio of the compound to fumaric acid is from about1.0:0.4 to about 1.0:0.7.
 5. A co-crystal of (a) a compound which is

and (b) fumaric acid, wherein said co-crystal is characterized by anx-ray powder diffraction pattern comprising a peak at each of 6.5, 12.5,16.8, and 25.3 degrees 2θ±0.2° when measured using CuKα radiation. 6.The co-crystal of claim 5, wherein said co-crystal is characterized byan x-ray powder diffraction pattern further comprising peaks at 8.6,14.0, and 18.7 degrees 2θ±0.2° when measured using CuKα radiation. 7.The co-crystal of claim 5, wherein the molar ratio of the compound tofumaric acid is from about 1.0:0.4 to about 1.0:0.7.
 8. A productobtained from a process comprising a step of combining a compound offormula

with fumaric acid, wherein said product is characterized by a CP/MAS ¹³CNMR spectrum comprising peaks with a chemical shift of 171.5±0.2 ppm,170.3±0.2 ppm, and 135.6±0.2 ppm when measured by the CP/MAS ¹³C NMRprocedure described in Example
 10. 9. The product of claim 8, whereinsaid product is characterized by a CP/MAS¹³C NMR spectrum furthercomprising a peak with a chemical shift of 72.2±0.2 ppm when measured bythe CP/MAS ¹³C NMR procedure described in Example
 10. 10. The product ofclaim 8, wherein said product is characterized by a CP/MAS ¹³C NMRspectrum further comprising peaks with a chemical shift of 72.2±0.2 ppmand 15.1±0.2 ppm when measured by the CP/MAS ¹³C NMR procedure describedin Example
 10. 11. The product of claim 8, wherein the molar ratio ofthe compound to fumaric acid is about 1.0:0.5.
 12. A product obtainedfrom a process comprising a step of combining a compound of formula

with fumaric acid, wherein said product is characterized by an x-raypowder diffraction pattern comprising a peak at each of 6.5, 12.5, 16.8,and 25.3 degrees 2θ±0.2° when measured using CuKα radiation.
 13. Theproduct of claim 12, wherein said product is characterized by an x-raypowder diffraction pattern further comprising peaks at 8.6, 14.0, and18.7 degrees 2θ±0.2° when measured using CuKα radiation.
 14. The productof claim 12, wherein the molar ratio of the compound to fumaric acid isabout 1.0:0.5.
 15. A pharmaceutical composition comprising theco-crystal of claim 1 and a pharmaceutically acceptable carrier orexcipient.
 16. A method for treating inflammatory pain, pain associatedwith osteoarthritis, or neuropathic pain in an animal, comprisingadministering to an animal in need thereof, an effective amount of theco-crystal of claim
 1. 17. A method of inhibiting TRPV1 function in acell comprising contacting a cell capable of expressing TRPV1 with aneffective amount of the co-crystal of claim
 1. 18. A pharmaceuticalcomposition comprising the co-crystal of claim 4 and a pharmaceuticallyacceptable carrier or excipient.
 19. A method for treating inflammatorypain, pain associated with osteoarthritis, or neuropathic pain in ananimal, comprising administering to an animal in need thereof, aneffective amount of the co-crystal of claim
 4. 20. A method ofinhibiting TRPV1 function in a cell comprising contacting a cell capableof expressing TRPV1 with an effective amount of the co-crystal of claim4.
 21. A pharmaceutical composition comprising the co-crystal of claim 5and a pharmaceutically acceptable carrier or excipient.
 22. A method fortreating inflammatory pain, pain associated with osteoarthritis, orneuropathic pain in an animal, comprising administering to an animal inneed thereof, an effective amount of the co-crystal of claim
 5. 23. Amethod of inhibiting TRPV1 function in a cell comprising contacting acell capable of expressing TRPV1 with an effective amount of theco-crystal of claim
 5. 24. A pharmaceutical composition comprising theco-crystal of claim 7 and a pharmaceutically acceptable carrier orexcipient.
 25. A method for treating inflammatory pain, pain associatedwith osteoarthritis, or neuropathic pain in an animal, comprisingadministering to an animal in need thereof, an effective amount of theco-crystal of claim
 7. 26. A method of inhibiting TRPV1 function in acell comprising contacting a cell capable of expressing TRPV1 with aneffective amount of the co-crystal of claim
 7. 27. The co-crystal ofclaim 1, wherein the molar ratio of the compound to fumaric acid isabout 1.0:0.5.
 28. A method for treating inflammatory pain, painassociated with osteoarthritis, or neuropathic pain in an animal,comprising administering to an animal in need thereof, an effectiveamount of the co-crystal of claim
 27. 29. The co-crystal of claim 5,wherein the molar ratio of the compound to fumaric acid is about1.0:0.5.
 30. A method for treating inflammatory pain, pain associatedwith osteoarthritis, or neuropathic pain in an animal, comprisingadministering to an animal in need thereof, an effective amount of theco-crystal of claim
 29. 31. The product of claim 8, wherein the molarratio of the compound to fumaric acid is from about 1.0:0.4 to about1.0:0.7.
 32. The product of claim 12, wherein the molar ratio of thecompound to fumaric acid is from about 1.0:0.4 to about 1.0:0.7.
 33. Amethod for treating inflammatory pain, pain associated withosteoarthritis, or neuropathic pain in an animal, comprisingadministering to an animal in need thereof, an effective amount of theproduct of claim
 11. 34. A method for treating inflammatory pain, painassociated with osteoarthritis, or neuropathic pain in an animal,comprising administering to an animal in need thereof an effectiveamount of the product of claim 14.